X-ray crystallographic structure of a complex between a synthetic protease of human immunodeficiency virus 1 and a substrate-based hydroxyethylamine inhibitor.
X-ray crystallographic structure of a complex between a synthetic protease of human immunodeficiency virus 1 and a substrate-based hydroxyethylamine inhibitor.
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DOI：
10.1073/pnas.87.22.8805
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发表时间：
1990-11
影响因子：
11.1
通讯作者：
A. Swain;M. Miller;Jeremy J Green;D. Rich;J. Schneider;S. Kent;A. Wlodawer
中科院分区：
文献类型：
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作者：
A. Swain;M. Miller;Jeremy J Green;D. Rich;J. Schneider;S. Kent;A. Wlodawer
化学合成的人类免疫缺陷病毒1型蛋白酶与活性位点结合的七肽衍生抑制剂的晶体复合物的结构已经确定。抑制剂JG-365的序列为ac - ser - leu - asn - ph -psi[CH(OH)CH2N]-Pro-Ile-Val-OMe；Ki值为0.24 nM。羟基乙胺部分取代了底物正常的可剪切键，被认为是模拟了一个四面体反应中间体。在2.4 A分辨率下，利用约束最小二乘法将配合物的结构细化到R因子0.146，键长的均方根偏差为0.02 A，键角为4。结合的抑制剂非对映体在羟乙胺手性碳上具有S构型，羟基位于活性位点天冬氨酸羧基之间，在氢键距离内。将这种结构与减少的肽键抑制剂-蛋白酶复合物进行比较，表明这些接触赋予了JG-365特殊的结合强度。
The structure of a crystal complex of the chemically synthesized protease of human immunodeficiency virus 1 with a heptapeptide-derived inhibitor bound in the active site has been determined. The sequence of the inhibitor JG-365 is Ac-Ser-Leu-Asn-Phe-psi[CH(OH)CH2N]-Pro-Ile-Val-OMe; the Ki is 0.24 nM. The hydroxyethylamine moiety, in place of the normal scissile bond of the substrate, is believed to mimic a tetrahedral reaction intermediate. The structure of the complex has been refined to an R factor of 0.146 at 2.4-A resolution by using restrained least squares with rms deviations in bond lengths of 0.02 A and bond angles of 4. The bound inhibitor diastereomer has the S configuration at the hydroxyethylamine chiral carbon, and the hydroxyl group is positioned between the active site aspartate carboxyl groups within hydrogen bonding distance. Comparison of this structure with a reduced peptide bond inhibitor-protease complex indicates that these contacts confer the exceptional binding strength of JG-365.