3T3C

Structure of HIV PR resistant patient derived mutant (comprising 22 mutations) in complex with DRV

3T3C の概要

• エントリーDOI: 10.2210/pdb3t3c/pdb
• 分子名称: HIV-1 protease, (3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YL(1S,2R)-3-[[(4-AMINOPHENYL)SULFONYL](ISOBUTYL)AMINO]-1-BENZYL-2-HYDROXYPROPYLCARBAMATE, BETA-MERCAPTOETHANOL, ... (5 entities in total)
• 機能のキーワード: peptidase, viral particle, hydrolase
• 由来する生物種: Human immunodeficiency virus type 1 (HIV-1)
• 細胞内の位置: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P03367
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22240.96

構造登録者

Rezacova, P.,Kozisek, M.,Konvalinka, J.,Saskova, K.G. (登録日: 2011-07-25, 公開日: 2012-06-20, 最終更新日: 2024-02-28)

主引用文献

Kozisek, M.,Henke, S.,Saskova, K.G.,Jacobs, G.B.,Schuch, A.,Buchholz, B.,Muller, V.,Krausslich, H.G.,Rezacova, P.,Konvalinka, J.,Bodem, J.
Mutations in HIV-1 gag and pol Compensate for the Loss of Viral Fitness Caused by a Highly Mutated Protease.
Antimicrob.Agents Chemother., 56:4320-4330, 2012

PubMed Abstract: During the last few decades, the treatment of HIV-infected patients by highly active antiretroviral therapy, including protease inhibitors (PIs), has become standard. Here, we present results of analysis of a patient-derived, multiresistant HIV-1 CRF02_AG recombinant strain with a highly mutated protease (PR) coding sequence, where up to 19 coding mutations have accumulated in the PR. The results of biochemical analysis in vitro showed that the patient-derived PR is highly resistant to most of the currently used PIs and that it also exhibits very poor catalytic activity. Determination of the crystal structure revealed prominent changes in the flap elbow region and S1/S1' active site subsites. While viral loads in the patient were found to be high, the insertion of the patient-derived PR into a HIV-1 subtype B backbone resulted in reduction of infectivity by 3 orders of magnitude. Fitness compensation was not achieved by elevated polymerase (Pol) expression, but the introduction of patient-derived gag and pol sequences in a CRF02_AG backbone rescued viral infectivity to near wild-type (wt) levels. The mutations that accumulated in the vicinity of the processing sites spanning the p2/NC, NC/p1, and p6pol/PR proteins lead to much more efficient hydrolysis of corresponding peptides by patient-derived PR in comparison to the wt enzyme. This indicates a very efficient coevolution of enzyme and substrate maintaining high viral loads in vivo under constant drug pressure.

PubMed: 22644035
DOI: 10.1128/AAC.00465-12

実験手法

X-RAY DIFFRACTION (2.1 Å)