Structural and Biochemical Studies of Inhibitor Binding to Human Cytomegalovirus Protease

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• 作者：Reza Khayat ; Renu Batra ; Chungeng Qian ; Teddy Halmos ; Murray Bailey ; and Liang Tong
• 刊名：Biochemistry
• 出版年：2003
• 出版时间：February 4, 2003
• 年：2003
• 卷：42
• 期：4
• 页码：885 - 891
• 全文大小：611K
• 年卷期：v.42,no.4(February 4, 2003)
• ISSN：1520-4995

文摘

Herpesvirus protease is required for the life cycle of the virus and is an attractive target forthe design and development of new anti-herpes agents. The protease belongs to a new class of serineproteases, with a novel backbone fold and a unique Ser-His-His catalytic triad. Here we report thecrystal structures of human cytomegalovirus protease in complex with two peptidomimetic inhibitors.The structures reveal a new hydrogen-bonding interaction between the main chain carbonyl of the P₅residue and the main chain amide of amino acid 137 of the protease, which is important for the bindingaffinity of the inhibitor. Conformational flexibility was observed in the S₃ pocket of the enzyme, and thisis supported by our characterization of several mutants in this pocket. One of the structures is at 2.5 Åresolution, allowing us for the first time to locate ordered solvent molecules in the inhibitor complex. Thepresence of two solvent molecules in the active site may have implications for the design of new inhibitorsagainst this enzyme. Favorable and stereospecific interactions have been established in the S₁' pocket forone of these inhibitors.