title: Drug resistance conferred by mutations outside the active site through alterations in the dynamic and structural ensemble of HIV-1 protease.
abstract: HIV-1 protease inhibitors are part of the highly active antiretroviral therapy effectively used in the treatment of HIV infection and AIDS. Darunavir (DRV) is the most potent of these inhibitors, soliciting drug resistance only when a complex combination of mutations occur both inside and outside the protease active site. With few exceptions, the role of mutations outside the active site in conferring resistance remains largely elusive. Through a series of DRV-protease complex crystal structures, inhibition assays, and molecular dynamics simulations, we find that single and double site mutations outside the active site often associated with DRV resistance alter the structure and dynamic ensemble of HIV-1 protease active site. These alterations correlate with the observed inhibitor binding affinities for the mutants, and suggest a network hypothesis on how the effect of distal mutations are propagated to pivotal residues at the active site and may contribute to conferring drug resistance.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School , Worcester, Massachusetts 01605, United States.
authors.forename: Debra A
authors.initials: DA
authors.lastname: Ragland
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Nalivaika
authors.forename: Madhavi N L
authors.initials: MN
authors.lastname: Nalam
authors.forename: Kristina L
authors.initials: KL
authors.lastname: Prachanronarong
authors.forename: Hong
authors.initials: H
authors.lastname: Cao
authors.forename: Rajintha M
authors.initials: RM
authors.lastname: Bandaranayake
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Cai
authors.forename: Nese
authors.initials: N
authors.lastname: Kurt-Yilmaz
authors.forename: Celia A
authors.initials: CA
authors.lastname: Schiffer
mesh_terms: D001665:Binding Sites; D000069454:Darunavir; D024882:Drug Resistance, Viral / Q000235:genetics*; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology*; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D016333:HIV Protease; D000069454:Darunavir
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