Drake R R, Neamati N, Hong H, Pilon A A, Sunthankar P, Hume S D, Milne G W, Pommier Y
Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4170-5. doi: 10.1073/pnas.95.8.4170.
HIV-1 integrase is essential for viral replication and can be inhibited by antiviral nucleotides. Photoaffinity labeling with the 3'-azido-3'-deoxythymidine (AZT) analog 3',5-diazido-2', 3'-dideoxyuridine 5'-monophosphate (5N3-AZTMP) and proteolytic mapping identified the amino acid 153-167 region of integrase as the site of photocrosslinking. Docking of 5N3-AZTMP revealed the possibility for strong hydrogen bonds between the inhibitor and lysines 156, 159, and 160 of the enzyme. Mutation of these residues reduced photocrosslinking selectively. This report elucidates the binding site of a nucleotide inhibitor of HIV-1 integrase, and possibly a component of the enzyme polynucleotide binding site.
HIV-1整合酶对病毒复制至关重要，且可被抗病毒核苷酸抑制。用3'-叠氮-3'-脱氧胸苷（AZT）类似物3',5-二叠氮-2',3'-二脱氧尿苷5'-单磷酸（5N3-AZTMP）进行光亲和标记及蛋白水解图谱分析确定了整合酶的153-167氨基酸区域为光交联位点。5N3-AZTMP的对接显示该抑制剂与酶的赖氨酸156、159和160之间可能形成强氢键。这些残基的突变选择性地降低了光交联。本报告阐明了HIV-1整合酶核苷酸抑制剂的结合位点，可能也是该酶多核苷酸结合位点的一个组成部分。
