- Title
- Allosteric modulation of conformational dynamics in human Hsp90α: a computational study
- Creator
- Penkler, David L, Atilgan, Canan, Tastan Bishop, Özlem
- Date
- 2017
- Type
- text
- Type
- article
- Identifier
- http://hdl.handle.net/10962/68531
- Identifier
- vital:29276
- Identifier
- http://dx.doi.org/10.1101/198341
- 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 co-chaperone association, presents as an attractive therapeutic strategy for Hsp90 associated pathologies. Here, we utilize homology modeling techniques to calculate full-length structures of human Hsp90α in closed and partially-open conformations. Atomistic simulations of these structures demonstrated that bound ATP stabilizes the dimer by ‘tensing’ each protomer, while ADP and apo configurations ‘relax’ the complex by increasing global flexibility. Dynamic residue network analysis revealed regions of the protein involved in intra-protein communication, and identified several overlapping key communication hubs that correlate with known functional sites. Perturbation response scanning analysis identified several potential residue sites capable of modulating conformational change in favour of interstate conversion. For the ATP-bound open conformation, these sites were found to overlap with known Aha1 and client binding sites, demonstrating how naturally occurring forces associated with co-factor binding could allosterically modulate conformational dynamics.
- Format
- 56 pages, pdf
- Language
- English
- Relation
- bioRxiv, Penkler, D.L., Atilgan, C. and Bishop, O.T., 2017. Allosteric Modulation of Conformational Dynamics in Human Hsp90?: A Computational Study. bioRxiv, p.198341., bioRxiv 1 56 October 2017 1549-960X
- Rights
- bioRxiv
- Rights
- Use of this resource is governed by the terms and conditions of the bioRxiv Open Access Statement
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Tastan Bishop, Ozlem (Prof)
RU Department of Biochemistry, Microbiology and Bioinformatics
SDG 03. Good Health and Well-Being
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