6OOS

HIV-1 Protease NL4-3 L90M Mutant in complex with darunavir

6OOS の概要

• エントリーDOI: 10.2210/pdb6oos/pdb
• 分子名称: NL4-3 PROTEASE, SULFATE ION, (3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YL(1S,2R)-3-[[(4-AMINOPHENYL)SULFONYL](ISOBUTYL)AMINO]-1-BENZYL-2-HYDROXYPROPYLCARBAMATE, ... (4 entities in total)
• 機能のキーワード: hiv, nl4-3 protease, drug resistance, protease inhibitor, hydrolase inhibitor complex, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Human immunodeficiency virus 1
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 45551.50

構造登録者

Henes, M.,Kosovrasti, K.,Lockbaum, G.J.,Leidner, F.,Nachum, G.S.,Nalivaika, E.A.,Bolon, D.N.A.,KurtYilmaz, N.,Schiffer, C.A.,Whitfield, T.W. (登録日: 2019-04-23, 公開日: 2019-08-21, 最終更新日: 2023-10-11)

主引用文献

Henes, M.,Kosovrasti, K.,Lockbaum, G.J.,Leidner, F.,Nachum, G.S.,Nalivaika, E.A.,Bolon, D.N.A.,Kurt Yilmaz, N.,Schiffer, C.A.,Whitfield, T.W.
Molecular Determinants of Epistasis in HIV-1 Protease: Elucidating the Interdependence of L89V and L90M Mutations in Resistance.
Biochemistry, 58:3711-3726, 2019

PubMed Abstract: Protease inhibitors have the highest potency among antiviral therapies against HIV-1 infections, yet the virus can evolve resistance. Darunavir (DRV), currently the most potent Food and Drug Administration-approved protease inhibitor, retains potency against single-site mutations. However, complex combinations of mutations can confer resistance to DRV. While the interdependence between mutations within HIV-1 protease is key for inhibitor potency, the molecular mechanisms that underlie this control remain largely unknown. In this study, we investigated the interdependence between the L89V and L90M mutations and their effects on DRV binding. These two mutations have been reported to be positively correlated with one another in HIV-1 patient-derived protease isolates, with the presence of one mutation making the probability of the occurrence of the second mutation more likely. The focus of our investigation is a patient-derived isolate, with 24 mutations that we call "KY"; this variant includes the L89V and L90M mutations. Three additional KY variants with back-mutations, KY(V89L), KY(M90L), and the KY(V89L/M90L) double mutation, were used to experimentally assess the individual and combined effects of these mutations on DRV inhibition and substrate processing. The enzymatic assays revealed that the KY(V89L) variant, with methionine at residue 90, is highly resistant, but its catalytic function is compromised. When a leucine to valine mutation at residue 89 is present simultaneously with the L90M mutation, a rescue of catalytic efficiency is observed. Molecular dynamics simulations of these DRV-bound protease variants reveal how the L90M mutation induces structural changes throughout the enzyme that undermine the binding interactions.

PubMed: 31386353
DOI: 10.1021/acs.biochem.9b00446

実験手法

X-RAY DIFFRACTION (1.9 Å)