tailieunhanh - Báo cáo khoa học: Molecular basis for substrate recognition and drug ˚ resistance from 1.1 to 1.6 A resolution crystal structures of HIV-1 protease mutants with substrate analogs

HIV-1 protease (PR) and two drug-resistant variants – PR with the V82A mutation (PRV82A) and PR with the I84V mutation (PRI84V) – were studied using reduced peptide analogs of five natural cleavage sites (CA-p2, p2-NC, p6 pol -PR, p1-p6 and NC-p1) to understand the structural and kine-tic changes. The common drug-resistant mutations V82A and I84V alter residues forming the substrate-binding site. Eight crystal structures were refined at resolutions of – A ˚ . | ềFEBS Journal Molecular basis for substrate recognition and drug resistance from to A resolution crystal structures of HIV-1 protease mutants with substrate analogs Yunfeng Tie1 Peter I. Boross2 3 Yuan-Fang Wang2 Laquasha Gaddis2 Fengling Liu2 Xianfeng Chen2 Jozsef Tozser3 Robert W. Harrison2 4 and Irene T. Weber1 2 1 Department of Chemistry Molecular Basis of Disease Georgia State University Atlanta GA USA 2 Department of Biology Molecular Basis of Disease Georgia State University Atlanta GA USA 3 Department of Biochemistry and Molecular Biology Faculty of Medicine University of Debrecen Hungary 4 Department of Computer Science Molecular Basis of Disease Georgia State University Atlanta GA USA Keywords catalysis crystal structure drug resistance HIV-1 protease substrate analog Correspondence I. T. Weber Department of Biology PO Box 4010 Georgia State University Atlanta GA 30302-4010 USA Fax 1 404 651 2509 Tel 1 404 651 0098 E-mail iweber@ Received 16 June 2005 revised 15 August 2005 accepted 18 August 2005 doi HIV-1 protease PR and two drug-resistant variants - PR with the V82A mutation PRV82A and PR with the I84V mutation PRI84V - were studied using reduced peptide analogs of five natural cleavage sites CA-p2 p2-NC p6pol-PR p1-p6 and NC-p1 to understand the structural and kinetic changes. The common drug-resistant mutations V82A and I84V alter residues forming the substrate-binding site. Eight crystal structures were refined at resolutions of A. Differences in the PR-analog interactions depended on the peptide sequence and were consistent with the relative inhibition. Analog p6pol-PR formed more hydrogen bonds of P2 Asn with PR and fewer van der Waals contacts at P1 Pro compared with those formed by CA-p2 or p2-NC in PR complexes. The P3 Gly in p1-p6 provided fewer van der Waals contacts and hydrogen bonds at P2-P3 and more water-mediated interactions. PRI84V showed reduced van der Waals interactions with

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