3PWR

HIV-1 Protease Mutant L76V complexed with Saquinavir

3PWR の概要

• エントリーDOI: 10.2210/pdb3pwr/pdb
• 関連するPDBエントリー: 3OXC
• 関連するBIRD辞書のPRD_ID: PRD_000454
• 分子名称: Protease, (2S)-N-[(2S,3R)-4-[(2S,3S,4aS,8aS)-3-(tert-butylcarbamoyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-3-hydroxy-1 -phenyl-butan-2-yl]-2-(quinolin-2-ylcarbonylamino)butanediamide, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: hiv-1, protease, mutation l76v, saquinavir, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Human immunodeficiency virus 1
• 細胞内の位置: Gag-Pol polyprotein: Host cell membrane ; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03367
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22896.35

構造登録者

Zhang, Y.,Weber, I.T. (登録日: 2010-12-08, 公開日: 2011-04-20, 最終更新日: 2023-09-13)

主引用文献

Louis, J.M.,Zhang, Y.,Sayer, J.M.,Wang, Y.F.,Harrison, R.W.,Weber, I.T.
The L76V Drug Resistance Mutation Decreases the Dimer Stability and Rate of Autoprocessing of HIV-1 Protease by Reducing Internal Hydrophobic Contacts.
Biochemistry, 50:4786-4795, 2011

PubMed Abstract: The mature HIV-1 protease (PR) bearing the L76V drug resistance mutation (PR(L76V)) is significantly less stable, with a >7-fold higher dimer dissociation constant (K(d)) of 71 ± 24 nM and twice the sensitivity to urea denaturation (UC(50) = 0.85 M) relative to those of PR. Differential scanning calorimetry showed decreases in T(m) of 12 °C for PR(L76V) in the absence of inhibitors and 5-7 °C in the presence of inhibitors darunavir (DRV), saquinavir (SQV), and lopinavir (LPV), relative to that of PR. Isothermal titration calorimetry gave a ligand dissociation constant of 0.8 nM for DRV, ∼160-fold higher than that of PR, consistent with DRV resistance. Crystal structures of PR(L76V) in complexes with DRV and SQV were determined at resolutions of 1.45-1.46 Å. Compared to the corresponding PR complexes, the mutated Val76 lacks hydrophobic interactions with Asp30, Lys45, Ile47, and Thr74 and exhibits closer interactions with Val32 and Val56. The bound DRV lacks one hydrogen bond with the main chain of Asp30 in PR(L76V) relative to PR, possibly accounting for the resistance to DRV. SQV shows slightly improved polar interactions with PR(L76V) compared to those with PR. Although the L76V mutation significantly slows the N-terminal autoprocessing of the precursor TFR-PR(L76V) to give rise to the mature PR(L76V), the coselected M46I mutation counteracts the effect by enhancing this rate but renders the TFR-PR(M46I/L76V) precursor less responsive to inhibition by 6 μM LPV while preserving inhibition by SQV and DRV. The correlation of lowered stability, higher K(d), and impaired autoprocessing with reduced internal hydrophobic contacts suggests a novel molecular mechanism for drug resistance.

PubMed: 21446746
DOI: 10.1021/bi200033z

実験手法

X-RAY DIFFRACTION (1.45 Å)