Allosteric Modulation of Human Hsp90α Conformational Dynamics:
- Penkler, David L, Atilgan, Canan, Tastan Bishop, Özlem
- Authors: Penkler, David L , Atilgan, Canan , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162936 , vital:40998 , https://doi.org/10.1021/acs.jcim.7b00630
- Description: Central to Hsp90’s biological function is its ability to interconvert between various conformational states. Drug targeting of Hsp90’s regulatory mechanisms, including its modulation by cochaperone association, presents as an attractive therapeutic strategy for Hsp90 associated pathologies. In this study, we utilized homology modeling techniques to calculate full-length structures of human Hsp90α in closed and partially open conformations and used these structures as a basis for several molecular dynamics based analyses aimed at elucidating allosteric mechanisms and modulation sites in human Hsp90α.
- Full Text:
- Date Issued: 2018
- Authors: Penkler, David L , Atilgan, Canan , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162936 , vital:40998 , https://doi.org/10.1021/acs.jcim.7b00630
- Description: Central to Hsp90’s biological function is its ability to interconvert between various conformational states. Drug targeting of Hsp90’s regulatory mechanisms, including its modulation by cochaperone association, presents as an attractive therapeutic strategy for Hsp90 associated pathologies. In this study, we utilized homology modeling techniques to calculate full-length structures of human Hsp90α in closed and partially open conformations and used these structures as a basis for several molecular dynamics based analyses aimed at elucidating allosteric mechanisms and modulation sites in human Hsp90α.
- Full Text:
- Date Issued: 2018
Aminoacyl tRNA synthetases as malarial drug targets: a comparative bioinformatics study
- Nyamai, Dorothy Wavinya, Tastan Bishop, Özlem
- Authors: Nyamai, Dorothy Wavinya , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148368 , vital:38733 , DOI: 10.1101/440891
- Description: Treatment of parasitic diseases has been challenging due to evolution of drug resistant parasites, and thus there is need to identify new class of drugs and drug targets. Protein translation is important for survival of malarial parasite, Plasmodium, and the pathway is present in all of its life cycle stages. Aminoacyl tRNA synthetases are primary enzymes in protein translation as they catalyse amino acid addition to the cognate tRNA. This study sought to understand differences between Plasmodium and human aminoacyl tRNA synthetases through bioinformatics analysis.
- Full Text:
- Date Issued: 2018
- Authors: Nyamai, Dorothy Wavinya , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148368 , vital:38733 , DOI: 10.1101/440891
- Description: Treatment of parasitic diseases has been challenging due to evolution of drug resistant parasites, and thus there is need to identify new class of drugs and drug targets. Protein translation is important for survival of malarial parasite, Plasmodium, and the pathway is present in all of its life cycle stages. Aminoacyl tRNA synthetases are primary enzymes in protein translation as they catalyse amino acid addition to the cognate tRNA. This study sought to understand differences between Plasmodium and human aminoacyl tRNA synthetases through bioinformatics analysis.
- Full Text:
- Date Issued: 2018
Characterizing early drug resistance-related events using geometric ensembles from HIV protease dynamics:
- Amamuddy, Olivier S, Bishop, Nigel T, Tastan Bishop, Özlem
- Authors: Amamuddy, Olivier S , Bishop, Nigel T , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148126 , vital:38712 , DOI: 10.1038/s41598-018-36041-8
- Description: The use of antiretrovirals (ARVs) has drastically improved the life quality and expectancy of HIV patients since their introduction in health care. Several millions are still afflicted worldwide by HIV and ARV resistance is a constant concern for both healthcare practitioners and patients, as while treatment options are finite, the virus constantly adapts via complex mutation patterns to select for resistant strains under the pressure of drug treatment. The HIV protease is a crucial enzyme for viral maturation and has been a game changing drug target since the first application. Due to similarities in protease inhibitor designs, drug cross-resistance is not uncommon across ARVs of the same class.
- Full Text:
- Date Issued: 2018
- Authors: Amamuddy, Olivier S , Bishop, Nigel T , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148126 , vital:38712 , DOI: 10.1038/s41598-018-36041-8
- Description: The use of antiretrovirals (ARVs) has drastically improved the life quality and expectancy of HIV patients since their introduction in health care. Several millions are still afflicted worldwide by HIV and ARV resistance is a constant concern for both healthcare practitioners and patients, as while treatment options are finite, the virus constantly adapts via complex mutation patterns to select for resistant strains under the pressure of drug treatment. The HIV protease is a crucial enzyme for viral maturation and has been a game changing drug target since the first application. Due to similarities in protease inhibitor designs, drug cross-resistance is not uncommon across ARVs of the same class.
- Full Text:
- Date Issued: 2018
Comparing sequence and structure of falcipains and human homologs at prodomain and catalytic active site for malarial peptide-based inhibitor design:
- Musyoka, Thommas M, Njuguna, Joyce N, Tastan Bishop, Özlem
- Authors: Musyoka, Thommas M , Njuguna, Joyce N , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148392 , vital:38735 , DOI: 10.1101/381566
- Description: Falcipains are major cysteine proteases of Plasmodium falciparum involved in haemoglobin degradation and remain attractive anti-malarial drug targets. Several inhibitors against these proteases have been identified, yet none of them has been approved for malaria treatment. Other Plasmodium species also possess highly homologous proteins to falcipains. For selective therapeutic targeting, identification of sequence and structure differences with homologous human cathepsins is necessary. The substrate processing activity of these proteins is tightly controlled via a prodomain segment occluding the active site which is chopped under low pH conditions exposing the catalytic site. Current work characterizes these proteases to identify residues mediating the prodomain regulatory function for the design of peptide based anti-malarial inhibitors.
- Full Text:
- Date Issued: 2018
- Authors: Musyoka, Thommas M , Njuguna, Joyce N , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148392 , vital:38735 , DOI: 10.1101/381566
- Description: Falcipains are major cysteine proteases of Plasmodium falciparum involved in haemoglobin degradation and remain attractive anti-malarial drug targets. Several inhibitors against these proteases have been identified, yet none of them has been approved for malaria treatment. Other Plasmodium species also possess highly homologous proteins to falcipains. For selective therapeutic targeting, identification of sequence and structure differences with homologous human cathepsins is necessary. The substrate processing activity of these proteins is tightly controlled via a prodomain segment occluding the active site which is chopped under low pH conditions exposing the catalytic site. Current work characterizes these proteases to identify residues mediating the prodomain regulatory function for the design of peptide based anti-malarial inhibitors.
- Full Text:
- Date Issued: 2018
Establishment of “The South African Bioinformatics Student Council” and activity highlights:
- Rafael, Candice Nancy, Ambler, Jon, Niehaus, Antoinette, Ross, James, Tastan Bishop, Özlem
- Authors: Rafael, Candice Nancy , Ambler, Jon , Niehaus, Antoinette , Ross, James , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148250 , vital:38723 , https://doi.org/10.14806/ej.23.0.903
- Description: The South African Society for Bioinformatics1 (SASBi) was officially formed in September 2012 during a joint Congress with the South African Genetics Society (SAGS). Prior to this there was no official body to represent bioinformatic researchers and students in the country. The establishment of SASBi also led to the establishment of the Student Society as a platform for students to meet and discuss their research activities, but also to socialise and broaden their network of knowledge and friendships. A small group of students joined as volunteers to pioneer and set up a SASBi Student Council (SASBiSC). As a first step, one representative, selected from the attendees present at the first Joint Congress of SASBi and SAGS, was elected to the main SASBi Council.
- Full Text:
- Date Issued: 2018
- Authors: Rafael, Candice Nancy , Ambler, Jon , Niehaus, Antoinette , Ross, James , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148250 , vital:38723 , https://doi.org/10.14806/ej.23.0.903
- Description: The South African Society for Bioinformatics1 (SASBi) was officially formed in September 2012 during a joint Congress with the South African Genetics Society (SAGS). Prior to this there was no official body to represent bioinformatic researchers and students in the country. The establishment of SASBi also led to the establishment of the Student Society as a platform for students to meet and discuss their research activities, but also to socialise and broaden their network of knowledge and friendships. A small group of students joined as volunteers to pioneer and set up a SASBi Student Council (SASBiSC). As a first step, one representative, selected from the attendees present at the first Joint Congress of SASBi and SAGS, was elected to the main SASBi Council.
- Full Text:
- Date Issued: 2018
Hepatitis C and HIV Coinfection in Developing Countries:
- Authors: Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/148228 , vital:38721 , ISBN 9780128032343 , https://books.google.co.za/books?id=XSmlCgAAQBAJanddq=hepatitis+c+in+developing+countriesandsource=gbs_navlinks_s
- Description: Because of the common routes of transmission, hepatitis C virus (HCV) coinfection with HIV is frequent. Of the 36.6 million HIV-infected individuals worldwide, about 25% are also coinfected with HCV. Developing countries face the greatest burden of coinfection. HIV infection has been shown to have a significant impact on the progression of chronic HCV, with a higher risk of cirrhosis and hepatocellular carcinoma (HCC). Because of the improvements in the management and treatment of HIV/AIDS in resource-limited countries, HCV/HIV coinfection is becoming a significant clinical problem and a major cause of morbidity and mortality. HCV/HIV coinfection is characterized by aggressive hepatic fibrogenesis, incidence of cirrhosis, and HCC. HCC is currently a major cause for liver-related deaths in HIV patients. Viral eradication has been difficult to attain with interferon and ribavirin therapies. Novel therapies with direct-acting antiviral agents have been promising for this population. However, access to such expensive regimen is far beyond the capabilities of most resource-limited countries. Yet, studies lag behind those for HCV monoinfection.
- Full Text:
- Date Issued: 2018
- Authors: Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/148228 , vital:38721 , ISBN 9780128032343 , https://books.google.co.za/books?id=XSmlCgAAQBAJanddq=hepatitis+c+in+developing+countriesandsource=gbs_navlinks_s
- Description: Because of the common routes of transmission, hepatitis C virus (HCV) coinfection with HIV is frequent. Of the 36.6 million HIV-infected individuals worldwide, about 25% are also coinfected with HCV. Developing countries face the greatest burden of coinfection. HIV infection has been shown to have a significant impact on the progression of chronic HCV, with a higher risk of cirrhosis and hepatocellular carcinoma (HCC). Because of the improvements in the management and treatment of HIV/AIDS in resource-limited countries, HCV/HIV coinfection is becoming a significant clinical problem and a major cause of morbidity and mortality. HCV/HIV coinfection is characterized by aggressive hepatic fibrogenesis, incidence of cirrhosis, and HCC. HCC is currently a major cause for liver-related deaths in HIV patients. Viral eradication has been difficult to attain with interferon and ribavirin therapies. Novel therapies with direct-acting antiviral agents have been promising for this population. However, access to such expensive regimen is far beyond the capabilities of most resource-limited countries. Yet, studies lag behind those for HCV monoinfection.
- Full Text:
- Date Issued: 2018
Homology modeling and docking of AahII-Nanobody complexes reveal the epitope binding site on AahII scorpion toxin
- Ksouri, Ayoub, Ghedira, Kais, Abderrazek, Rahma Ben, Shankar, B A Gowri, Benkahla, Alia, Tastan Bishop, Özlem, Bouhaouala-Zahar, Balkis
- Authors: Ksouri, Ayoub , Ghedira, Kais , Abderrazek, Rahma Ben , Shankar, B A Gowri , Benkahla, Alia , Tastan Bishop, Özlem , Bouhaouala-Zahar, Balkis
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/124604 , vital:35637 , https://doi.10.1016/j.bbrc.2018.01.036
- Description: Scorpion envenoming and its treatment is a public health problem in many parts of the world due to highly toxic venom polypeptides diffusing rapidly within the body of severely envenomed victims. Recently, 38 AahII-specific Nanobody sequences (Nbs) were retrieved from which the performance of NbAahII10 nanobody candidate, to neutralize the most poisonous venom compound namely AahII acting on sodium channels, was established. Herein, structural computational approach is conducted to elucidate the Nb-AahII interactions that support the biological characteristics, using Nb multiple sequence alignment (MSA) followed by modeling and molecular docking investigations (RosettaAntibody, ZDOCK software tools). Sequence and structural analysis showed two dissimilar residues of NbAahII10 CDR1 (Tyr27 and Tyr29) and an inserted polar residue Ser30 that appear to play an important role. Indeed, CDR3 region of NbAahII10 is characterized by a specific Met104 and two negatively chargedresidues Asp115 and Asp117. Complex dockings reveal that NbAahII17 and NbAahII38 share one common binding site on the surface of the AahII toxin divergent from the NbAahII10 one's. At least, a couple of NbAahII10 e AahII residue interactions (Gln38 e Asn44 and Arg62, His64, respectively) are mainly involved in the toxic AahII binding site. Altogether, this study gives valuable insights in the design and development of next generation of antivenom.
- Full Text:
- Date Issued: 2018
- Authors: Ksouri, Ayoub , Ghedira, Kais , Abderrazek, Rahma Ben , Shankar, B A Gowri , Benkahla, Alia , Tastan Bishop, Özlem , Bouhaouala-Zahar, Balkis
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/124604 , vital:35637 , https://doi.10.1016/j.bbrc.2018.01.036
- Description: Scorpion envenoming and its treatment is a public health problem in many parts of the world due to highly toxic venom polypeptides diffusing rapidly within the body of severely envenomed victims. Recently, 38 AahII-specific Nanobody sequences (Nbs) were retrieved from which the performance of NbAahII10 nanobody candidate, to neutralize the most poisonous venom compound namely AahII acting on sodium channels, was established. Herein, structural computational approach is conducted to elucidate the Nb-AahII interactions that support the biological characteristics, using Nb multiple sequence alignment (MSA) followed by modeling and molecular docking investigations (RosettaAntibody, ZDOCK software tools). Sequence and structural analysis showed two dissimilar residues of NbAahII10 CDR1 (Tyr27 and Tyr29) and an inserted polar residue Ser30 that appear to play an important role. Indeed, CDR3 region of NbAahII10 is characterized by a specific Met104 and two negatively chargedresidues Asp115 and Asp117. Complex dockings reveal that NbAahII17 and NbAahII38 share one common binding site on the surface of the AahII toxin divergent from the NbAahII10 one's. At least, a couple of NbAahII10 e AahII residue interactions (Gln38 e Asn44 and Arg62, His64, respectively) are mainly involved in the toxic AahII binding site. Altogether, this study gives valuable insights in the design and development of next generation of antivenom.
- Full Text:
- Date Issued: 2018
HUMA: A platform for the analysis of genetic variation in humans
- Brown, David K, Tastan Bishop, Özlem
- Authors: Brown, David K , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/124653 , vital:35642 , https://doi.10.1002/humu.23334
- Description: The completion of the human genome project at the beginning of the 21st century, along with the rapid advancement of sequencing technologies thereafter, has resulted in exponential growth of biological data. In genetics, this has given rise to numerous variation databases, created to store and annotate the ever-expanding dataset of known mutations. Usually, these databases focus on variation at the sequence level. Few databases focus on the analysis of variation at the 3D level, that is, mapping, visualizing, and determining the effects of variation in protein structures. Additionally, these Web servers seldom incorporate tools to help analyze these data. Here, we present the Human Mutation Analysis (HUMA) Web server and database. HUMA integrates sequence, structure, variation, and disease data into a single, connected database. A user-friendly interface provides click-based data access and visualization, whereas a RESTfulWebAPI provides programmatic access to the data. Tools have been integrated into HUMA to allow initial analyses to be carried out on the server. Furthermore, users can upload their private variation datasets, which are automatically mapped to public data and can be analyzed using the integrated tools. HUMA is freely accessible at https://huma.rubi.ru.ac.za.
- Full Text:
- Date Issued: 2018
- Authors: Brown, David K , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/124653 , vital:35642 , https://doi.10.1002/humu.23334
- Description: The completion of the human genome project at the beginning of the 21st century, along with the rapid advancement of sequencing technologies thereafter, has resulted in exponential growth of biological data. In genetics, this has given rise to numerous variation databases, created to store and annotate the ever-expanding dataset of known mutations. Usually, these databases focus on variation at the sequence level. Few databases focus on the analysis of variation at the 3D level, that is, mapping, visualizing, and determining the effects of variation in protein structures. Additionally, these Web servers seldom incorporate tools to help analyze these data. Here, we present the Human Mutation Analysis (HUMA) Web server and database. HUMA integrates sequence, structure, variation, and disease data into a single, connected database. A user-friendly interface provides click-based data access and visualization, whereas a RESTfulWebAPI provides programmatic access to the data. Tools have been integrated into HUMA to allow initial analyses to be carried out on the server. Furthermore, users can upload their private variation datasets, which are automatically mapped to public data and can be analyzed using the integrated tools. HUMA is freely accessible at https://huma.rubi.ru.ac.za.
- Full Text:
- Date Issued: 2018
MODE-TASK: Large-scale protein motion tools
- Ross, Caroline J, Nizami, B, Glenister, Michael, Amamuddy, Olivier S, Atilgan, Ali R, Atilgan, Canan, Tastan Bishop, Özlem
- Authors: Ross, Caroline J , Nizami, B , Glenister, Michael , Amamuddy, Olivier S , Atilgan, Ali R , Atilgan, Canan , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/125206 , vital:35746 , http://dx.doi.org/10.1101/217505
- Description: Conventional analysis of molecular dynamics (MD) trajectories may not identify global motions of macromolecules. Normal Mode Analysis (NMA) and Principle Component Analysis (PCA) are two popular methods to quantify large-scale motions, and find the “essential motions”; and have been applied to problems such as drug resistant mutations (Nizami et al., 2016) and viral capsid expansion (Hsieh et al., 2016). MODE-TASK is an array of tools to analyse and compare protein dynamics obtained from MD simulations and/or coarse grained elastic network models. Users may perform standard PCA, kernel and incremental PCA (IPCA). Data reduction techniques (Multidimensional Scaling (MDS) and t-Distributed Stochastics Neighbor Embedding (t-SNE)) are implemented. Users may analyse normal modes by constructing elastic network models (ENMs) of a protein complex. A novel coarse graining approach extends its application to large biological assemblies.
- Full Text:
- Date Issued: 2018
- Authors: Ross, Caroline J , Nizami, B , Glenister, Michael , Amamuddy, Olivier S , Atilgan, Ali R , Atilgan, Canan , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/125206 , vital:35746 , http://dx.doi.org/10.1101/217505
- Description: Conventional analysis of molecular dynamics (MD) trajectories may not identify global motions of macromolecules. Normal Mode Analysis (NMA) and Principle Component Analysis (PCA) are two popular methods to quantify large-scale motions, and find the “essential motions”; and have been applied to problems such as drug resistant mutations (Nizami et al., 2016) and viral capsid expansion (Hsieh et al., 2016). MODE-TASK is an array of tools to analyse and compare protein dynamics obtained from MD simulations and/or coarse grained elastic network models. Users may perform standard PCA, kernel and incremental PCA (IPCA). Data reduction techniques (Multidimensional Scaling (MDS) and t-Distributed Stochastics Neighbor Embedding (t-SNE)) are implemented. Users may analyse normal modes by constructing elastic network models (ENMs) of a protein complex. A novel coarse graining approach extends its application to large biological assemblies.
- Full Text:
- Date Issued: 2018
Modulation of human Hsp90α conformational dynamics by allosteric ligand interaction at the c-terminal domain:
- Penkler, David L, Tastan Bishop, Özlem
- Authors: Penkler, David L , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148402 , vital:38736 , DOI: 10.1101/386755
- Description: Recent years have seen heat shock protein 90 kDa (Hsp90) attract significant interest as a viable drug target, particularly for cancer. To date, designed inhibitors that target the ATPase domain demonstrate potent anti-proliferative effects, but have failed clinical trials due to high levels of associated toxicity. To circumvent this, the focus has shifted away from the ATPase domain. One option involves modulation of the protein through allosteric activation/inhibition. Here, we propose a novel approach: we use previously obtained information via residue perturbation scanning coupled with dynamic residue network analysis to identify allosteric drug targeting sites for inhibitor docking.
- Full Text:
- Date Issued: 2018
- Authors: Penkler, David L , Tastan Bishop, Özlem
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148402 , vital:38736 , DOI: 10.1101/386755
- Description: Recent years have seen heat shock protein 90 kDa (Hsp90) attract significant interest as a viable drug target, particularly for cancer. To date, designed inhibitors that target the ATPase domain demonstrate potent anti-proliferative effects, but have failed clinical trials due to high levels of associated toxicity. To circumvent this, the focus has shifted away from the ATPase domain. One option involves modulation of the protein through allosteric activation/inhibition. Here, we propose a novel approach: we use previously obtained information via residue perturbation scanning coupled with dynamic residue network analysis to identify allosteric drug targeting sites for inhibitor docking.
- Full Text:
- Date Issued: 2018
No evidence for association between APOL1 kidney disease risk alleles and Human African Trypanosomiasis in two Ugandan populations:
- Kimuda, Magambo P, Noyes, Harry, Mulindwa, Julius, Enyaru, John, Alibu, Vincent P, Sidibe, Issa, Mumba Ngoyi, Dieuodonne, Hertz-Fowler, Christiane, MacLeod, Annette, Tastan Bishop, Özlem, Matovu, Enock
- Authors: Kimuda, Magambo P , Noyes, Harry , Mulindwa, Julius , Enyaru, John , Alibu, Vincent P , Sidibe, Issa , Mumba Ngoyi, Dieuodonne , Hertz-Fowler, Christiane , MacLeod, Annette , Tastan Bishop, Özlem , Matovu, Enock
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162924 , vital:40997 , https://doi.org/10.1371/journal.pntd.0006300
- Description: Human African trypanosomiasis (HAT) manifests as an acute form caused by Trypanosoma brucei rhodesiense (Tbr) and a chronic form caused by Trypanosoma brucei gambiense (Tbg). Previous studies have suggested a host genetic role in infection outcomes, particularly for APOL1. We have undertaken candidate gene association studies (CGAS) in a Ugandan Tbr and a Tbg HAT endemic area, to determine whether polymorphisms in IL10, IL8, IL4, HLAG, TNFA, TNX4LB, IL6, IFNG, MIF, APOL1, HLAA, IL1B, IL4R, IL12B, IL12R, HP, HPR, and CFH have a role in HAT.
- Full Text:
- Date Issued: 2018
- Authors: Kimuda, Magambo P , Noyes, Harry , Mulindwa, Julius , Enyaru, John , Alibu, Vincent P , Sidibe, Issa , Mumba Ngoyi, Dieuodonne , Hertz-Fowler, Christiane , MacLeod, Annette , Tastan Bishop, Özlem , Matovu, Enock
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162924 , vital:40997 , https://doi.org/10.1371/journal.pntd.0006300
- Description: Human African trypanosomiasis (HAT) manifests as an acute form caused by Trypanosoma brucei rhodesiense (Tbr) and a chronic form caused by Trypanosoma brucei gambiense (Tbg). Previous studies have suggested a host genetic role in infection outcomes, particularly for APOL1. We have undertaken candidate gene association studies (CGAS) in a Ugandan Tbr and a Tbg HAT endemic area, to determine whether polymorphisms in IL10, IL8, IL4, HLAG, TNFA, TNX4LB, IL6, IFNG, MIF, APOL1, HLAA, IL1B, IL4R, IL12B, IL12R, HP, HPR, and CFH have a role in HAT.
- Full Text:
- Date Issued: 2018
The determination of CHARMM force field parameters for the Mg2+ containing HIV-1 integrase:
- Musyoka, Thommas M, Tastan Bishop, Özlem, Lobb, Kevin A, Moses, Vuyani
- Authors: Musyoka, Thommas M , Tastan Bishop, Özlem , Lobb, Kevin A , Moses, Vuyani
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148139 , vital:38713 , DOI: 10.1016/j.cplett.2018.09.019
- Description: The HIV integrase enzyme is a validated drug target. However, its potential has remained largely unexploited until recently due to lack of structural and mechanistic information. Its catalytic core domain (CCD) is crucial for the viral-human DNA integration making integrase an ideal target for inhibitor design. However, in order to do so, force field parameters for the integrase magnesium ion need to be established. Quantum mechanical calculations were used to derive force field parameters which were validated through molecular dynamics studies. Our results show that the parameters determined accurately maintain the integrity of the metal pocket of the integrase CCD.
- Full Text:
- Date Issued: 2018
- Authors: Musyoka, Thommas M , Tastan Bishop, Özlem , Lobb, Kevin A , Moses, Vuyani
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148139 , vital:38713 , DOI: 10.1016/j.cplett.2018.09.019
- Description: The HIV integrase enzyme is a validated drug target. However, its potential has remained largely unexploited until recently due to lack of structural and mechanistic information. Its catalytic core domain (CCD) is crucial for the viral-human DNA integration making integrase an ideal target for inhibitor design. However, in order to do so, force field parameters for the integrase magnesium ion need to be established. Quantum mechanical calculations were used to derive force field parameters which were validated through molecular dynamics studies. Our results show that the parameters determined accurately maintain the integrity of the metal pocket of the integrase CCD.
- Full Text:
- Date Issued: 2018
The generation and characterisation of neutralising antibodies against the Theiler’s murine encephalomyelitis virus (TMEV) GDVII capsid reveals the potential binding site of the host cell co-receptor, heparan sulfate:
- Upfold, Nicole, Ross, Caroline J, Tastan Bishop, Özlem, Luke, Garry A, Knox, Caroline M
- Authors: Upfold, Nicole , Ross, Caroline J , Tastan Bishop, Özlem , Luke, Garry A , Knox, Caroline M
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148181 , vital:38717 , DOI: 10.1016/j.virusres.2017.11.017
- Description: The early stages of picornavirus capsid assembly and the host factors involved are poorly understood. Since the localisation of viral proteins in infected cells can provide information on their function, antibodies against purified Theiler's murine encephalomyelitis virus (TMEV) GDVII capsids were generated by immunisation of rabbits. The resultant anti-TMEV capsid antibodies recognised a C-terminal region of VP1 but not VP2 or VP3 by Western analysis. Examination of the sites of TMEV capsid assembly by indirect immunofluorescence and confocal microscopy showed that at 5 h post infection, capsid signal was diffusely cytoplasmic with strong perinuclear staining and moved into large punctate structures from 6 to 8 h post infection.
- Full Text:
- Date Issued: 2018
- Authors: Upfold, Nicole , Ross, Caroline J , Tastan Bishop, Özlem , Luke, Garry A , Knox, Caroline M
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148181 , vital:38717 , DOI: 10.1016/j.virusres.2017.11.017
- Description: The early stages of picornavirus capsid assembly and the host factors involved are poorly understood. Since the localisation of viral proteins in infected cells can provide information on their function, antibodies against purified Theiler's murine encephalomyelitis virus (TMEV) GDVII capsids were generated by immunisation of rabbits. The resultant anti-TMEV capsid antibodies recognised a C-terminal region of VP1 but not VP2 or VP3 by Western analysis. Examination of the sites of TMEV capsid assembly by indirect immunofluorescence and confocal microscopy showed that at 5 h post infection, capsid signal was diffusely cytoplasmic with strong perinuclear staining and moved into large punctate structures from 6 to 8 h post infection.
- Full Text:
- Date Issued: 2018
Unraveling the Motions behind Enterovirus 71 Uncoating:
- Ross, Caroline J, Atilgan, Ali R, Tastan Bishop, Özlem, Atilgan, Canan
- Authors: Ross, Caroline J , Atilgan, Ali R , Tastan Bishop, Özlem , Atilgan, Canan
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148158 , vital:38715 , DOI: 10.1016/j.bpj.2017.12.021
- Description: Enterovirus 71 can be a severe pathogen in small children and immunocompromised adults. Virus uncoating is a critical step in the infection of the host cell; however, the mechanisms that control this process remain poorly understood. We applied normal mode analysis and perturbation response scanning to several complexes of the virus capsid and present a coarse-graining approach to analyze the full capsid. We show that our method offers an alternative to expressing the system as a set of rigid blocks and accounts for the interconnection between nodes within each subunit and protein interfaces across the capsid. In our coarse-grained approach, the modes associated with capsid expansion are captured in the first three nondegenerate modes and correspond to the changes observed in structural studies of the virus. We show that the resolution of the analysis may be modified without losing information on the global motions leading to uncoating.
- Full Text:
- Date Issued: 2018
- Authors: Ross, Caroline J , Atilgan, Ali R , Tastan Bishop, Özlem , Atilgan, Canan
- Date: 2018
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148158 , vital:38715 , DOI: 10.1016/j.bpj.2017.12.021
- Description: Enterovirus 71 can be a severe pathogen in small children and immunocompromised adults. Virus uncoating is a critical step in the infection of the host cell; however, the mechanisms that control this process remain poorly understood. We applied normal mode analysis and perturbation response scanning to several complexes of the virus capsid and present a coarse-graining approach to analyze the full capsid. We show that our method offers an alternative to expressing the system as a set of rigid blocks and accounts for the interconnection between nodes within each subunit and protein interfaces across the capsid. In our coarse-grained approach, the modes associated with capsid expansion are captured in the first three nondegenerate modes and correspond to the changes observed in structural studies of the virus. We show that the resolution of the analysis may be modified without losing information on the global motions leading to uncoating.
- Full Text:
- Date Issued: 2018
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