Resistance from Afar: Distal Mutation V36M Allosterically Modulates the Active Site to Accentuate Drug Resistance in HCV NS3/4A Protease [preprint]
Authors
Ozen, AysegulLin, Kuan-Hung
Romano, Keith P.
Tavella, Davide
Newton, Alicia
Petropoulos, Christos J.
Huang, Wei
Aydin, Cihan
Schiffer, Celia A.
Document Type
PreprintPublication Date
2018-12-16Keywords
Molecular BiologyHepatitis C virus
drug resistance
non-active site mutations
Biochemistry
Enzymes and Coenzymes
Genetic Phenomena
Molecular Biology
Structural Biology
Viruses
Metadata
Show full item recordAbstract
Hepatitis C virus rapidly evolves, conferring resistance to direct acting antivirals. While resistance via active site mutations in the viral NS3/4A protease has been well characterized, the mechanism for resistance of non-active site mutations is unclear. R155K and V36M often co-evolve and while R155K alters the electrostatic network at the binding site, V36M is more than 13 Angstrom away. In this study the mechanism by which V36M confers resistance, in the context of R155K, is elucidated with drug susceptibility assays, crystal structures, and molecular dynamics (MD) simulations for three protease inhibitors: telaprevir, boceprevir and danoprevir. The R155K and R155K/V36M crystal structures differ in the α-2 helix and E2 strand near the active site, with alternative conformations at M36 and side chains of active site residues D168 and R123, revealing an allosteric coupling, which persists dynamically in MD simulations, between the distal mutation and the active site. This allosteric modulation validates the network hypothesis and elucidates how distal mutations confer resistance through propagation of conformational changes to the active site.Source
bioRxiv 452284; doi: https://doi.org/10.1101/45228. Link to preprint on bioRxiv service.
DOI
10.1101/452284Permanent Link to this Item
http://hdl.handle.net/20.500.14038/29378Rights
The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.Distribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/ae974a485f413a2113503eed53cd6c53
10.1101/452284
Scopus Count
Except where otherwise noted, this item's license is described as The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.