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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structure of HIV-1 protease in complex with potent inhibitor KNI-272 determined by high-resolution X-ray and neutron crystallography
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Structure of HIV-1 protease in complex with potent inhibitor KNI-272 determined by high-resolution X-ray and neutron crystallography

机译：高分辨率X射线和中子晶体学测定HIV-1蛋白酶与有效抑制剂KNI-272的配合物的结构

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摘要

HIV-1 protease is a dimeric aspartic protease that plays an essential role in viral replication. To further understand the catalytic mechanism and inhibitor recognition of HIV-1 protease, we need to determine the locations of key hydrogen atoms in the catalytic aspartates Asp-25 and Asp-125. The structure of HIV-1 protease in complex with transition-state analog KNI-272 was determined by combined neutron crystallography at 1.9-A resolution and X-ray crystallography at 1.4-A resolution. The resulting structural data show that the catalytic residue Asp-25 is protonated and that Asp-125 (the catalytic residue from the corresponding diad-related molecule) is deprotonated. The proton on Asp-25 makes a hydrogen bond with the carbonyl group of the allophenylnorstatine (Apns) group in KNI-272. The deprotonated Asp-125 bonds to the hydroxyl proton of Apns. The results provide direct experimental evidence for proposed aspects of the catalytic mechanism of HIV-1 protease and can therefore contribute substantially to the development of specific inhibitors for therapeutic application.
机译：HIV-1蛋白酶是一种二聚天冬氨酸蛋白酶，在病毒复制中起着至关重要的作用。为了进一步了解HIV-1蛋白酶的催化机理和抑制剂识别，我们需要确定催化天冬氨酸Asp-25和Asp-125中关键氢原子的位置。通过结合中子结晶学以1.9-A的分辨率和X射线晶体学以1.4-A的分辨率确定与过渡态类似物KNI-272结合的HIV-1蛋白酶的结构。所得的结构数据表明，催化残基Asp-25被质子化，并且Asp-125（来自相应的与二元体相关的分子的催化残基）被去质子。 Asp-25上的质子与KNI-272中的别苯基去甲他汀（Apns）基团的羰基形成氢键。去质子化的Asp-125与Apns的羟基质子结合。该结果为HIV-1蛋白酶催化机制的拟议方面提供了直接的实验证据，因此可以为治疗应用的特定抑制剂的开发做出重大贡献。

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  • 作者

    Motoyasu Adachi; Takashi Ohhara; Kazuo Kurihara; Taro Tamada; Eijiro Honjo; Nobuo Okazaki; Shigeki Arai; Yoshinari Shoyama; Kaname Kimura; Hiroyoshi Matsumura; Shigeru Sugiyama; Hiroaki Adachi; Kazufumi Takano; Yusuke Mori; Koushi Hidaka; Tooru Kimura; Yoshio Hayashi; Yoshiaki Kiso; Ryota Kuroki;

  • 作者单位

    Molecular Structural Biology Group, Quantum Beam Science Directorate, Japan Atomic Energy Agency, 2-4 Shirakata-Shirane, Tokai, Ibaraki 319-1195,Japan;

    Molecular Structural Biology Group, Quantum Beam Science Directorate, Japan Atomic Energy Agency, 2-4 Shirakata-Shirane, Tokai, Ibaraki 319-1195,Japan;

    Molecular Structural Biology Group, Quantum Beam Science Directorate, Japan Atomic Energy Agency, 2-4 Shirakata-Shirane, Tokai, Ibaraki 319-1195,Japan;

    Molecular Structural Biology Group, Quantum Beam Science Directorate, Japan Atomic Energy Agency, 2-4 Shirakata-Shirane, Tokai, Ibaraki 319-1195,Japan;

    Molecular Structural Biology Group, Quantum Beam Science Directorate, Japan Atomic Energy Agency, 2-4 Shirakata-Shirane, Tokai, Ibaraki 319-1195,Japan;

    Molecular Structural Biology Group, Quantum Beam Science Directorate, Japan Atomic Energy Agency, 2-4 Shirakata-Shirane, Tokai, Ibaraki 319-1195,Japan;

    Molecular Structural Biology Group, Quantum Beam Science Directorate, Japan Atomic Energy Agency, 2-4 Shirakata-Shirane, Tokai, Ibaraki 319-1195,Japan;

    Molecular Structural Biology Group, Quantum Beam Science Directorate, Japan Atomic Energy Agency, 2-4 Shirakata-Shirane, Tokai, Ibaraki 319-1195,Japan;

    Discovery Research Laboratories, Kirin Pharma Company, 3, Miyahara, Takasaki, Gunma 370-1295, Japan;

    Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan SOSHO Inc., 1-6-18 Honmachi, Chuo-ku, Osaka 541-0053, Japan;

    Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan;

    Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan SOSHO Inc., 1-6-18 Honmachi, Chuo-ku, Osaka 541-0053, Japan;

    Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan SOSHO Inc., 1-6-18 Honmachi, Chuo-ku, Osaka 541-0053, Japan;

    Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan SOSHO Inc., 1-6-18 Honmachi, Chuo-ku, Osaka 541-0053, Japan;

    Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Kyoto 607-8412, Japan;

    Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Kyoto 607-8412, Japan;

    Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Kyoto 607-8412, Japan;

    Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Kyoto 607-8412, Japan;

    Molecular Structural Biology Group, Quantum Beam Science Directorate, Japan Atomic Energy Agency, 2-4 Shirakata-Shirane, Tokai, Ibaraki 319-1195,Japan;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    drug target; neutron diffraction; reaction mechanism; transition-state analog;

    机译：药物目标中子衍射反应机理过渡态模拟;

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