4Q1X

Mutations Outside the Active Site of HIV-1 Protease Alter Enzyme Structure and Dynamic Ensemble of the Active Site to Confer Drug Resistance

Summary for 4Q1X

• Entry DOI: 10.2210/pdb4q1x/pdb
• Related: 4Q1W 4Q1Y
• Descriptor: ASPARTYL PROTEASE, (3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YL(1S,2R)-3-[[(4-AMINOPHENYL)SULFONYL](ISOBUTYL)AMINO]-1-BENZYL-2-HYDROXYPROPYLCARBAMATE, GLYCEROL, ... (5 entities in total)
• Functional Keywords: hiv-1 protease, aids, inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22394.36

Authors

Ragland, D.A.,Nalam, M.N.L.,Cao, H.,Nalivaika, E.A.,Cai, Y.,Kurt-Yilmaz, N.,Schiffer, C.A. (deposition date: 2014-04-04, release date: 2015-02-18, Last modification date: 2024-02-28)

Primary citation

Ragland, D.A.,Nalivaika, E.A.,Nalam, M.N.,Prachanronarong, K.L.,Cao, H.,Bandaranayake, R.M.,Cai, Y.,Kurt-Yilmaz, N.,Schiffer, C.A.
Drug resistance conferred by mutations outside the active site through alterations in the dynamic and structural ensemble of HIV-1 protease.
J.Am.Chem.Soc., 136:11956-11963, 2014

PubMed 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.

PubMed: 25091085
DOI: 10.1021/ja504096m

Experimental method

X-RAY DIFFRACTION (1.9 Å)