"Wide-open" 1.3 Å structure of a multidrug-resistant HIV-1 protease as a drug target
"Wide-open" 1.3 Å structure of a multidrug-resistant HIV-1 protease as a drug target
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DOI：
10.1016/j.str.2005.11.005
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发表时间：
2005-12-01
期刊：
影响因子：
5.7
通讯作者：
Kovari, LC
中科院分区：
文献类型：
--
作者：
Martin, P;Vickrey, JF;Kovari, LC
本报告研究了高度突变的临床多药耐药HIV-1蛋白酶的结构变化，在没有任何抑制剂的情况下，晶体结构已被解决为1.3埃分辨率。该蛋白酶变体在位置10、36、46、54、62、63、71、82、84和90处含有密码子突变，其赋予对蛋白酶抑制剂的抗性。野生型和变体之间的主要差异包括由M36 V突变引发并通过蛋白酶瓣中的额外突变扩增的结构变化，导致“完全开放”结构，其代表比野生型蛋白酶的“开放”结构宽8埃的开口。第二个结构变化是由L90 M突变引发的，导致23-32段重塑。蛋白酶的第三个关键结构变化是由于在位置82和84处从较长的氨基酸侧链突变为较短的氨基酸侧链。
This report examines structural changes in a highly mutated, clinical multidrug-resistant HIV-1 protease, and the crystal structure has been solved to 1.3 angstrom resolution in the absence of any inhibitor. This protease variant contains codon mutations at positions 10, 36, 46, 54, 62, 63, 71, 82, 84, and 90 that confer resistance to protease inhibitors. Major differences between the wild-type and the variant include a structural change initiated by the M36V mutation and amplified by additional mutations in the flaps of the protease, resulting in a "wide-open" structure that represents an opening that is 8 angstrom wider than the "open" structure of the wildtype protease. A second structural change is triggered by the L90M mutation that results in reshaping the 23-32 segment. A third key structural change of the protease is due to the mutations from longer to shorter amino acid side chains at positions 82 and 84.