Allosteric Modulation of Human Hsp90α Conformational Dynamics:
- 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.
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- Date Issued: 2018
Modulation of human Hsp90α conformational dynamics by allosteric ligand interaction at the c-terminal domain:
- 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