Structural and Biochemical Studies of Inhibitor Binding to Human Cytomegalovirus Protease
Herpesvirus protease is required for the life cycle of the virus and is an attractive target for the design and development of new anti-herpes agents. The protease belongs to a new class of serine proteases, with a novel backbone fold and a unique Ser−His−His catalytic triad. Here we report the crys...
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Veröffentlicht in: | Biochemistry 2003-02, Vol.42 (4), p.885-891 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | Herpesvirus protease is required for the life cycle of the virus and is an attractive target for the design and development of new anti-herpes agents. The protease belongs to a new class of serine proteases, with a novel backbone fold and a unique Ser−His−His catalytic triad. Here we report the crystal 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 P5 residue and the main chain amide of amino acid 137 of the protease, which is important for the binding affinity of the inhibitor. Conformational flexibility was observed in the S3 pocket of the enzyme, and this is supported by our characterization of several mutants in this pocket. One of the structures is at 2.5 Å resolution, allowing us for the first time to locate ordered solvent molecules in the inhibitor complex. The presence of two solvent molecules in the active site may have implications for the design of new inhibitors against this enzyme. Favorable and stereospecific interactions have been established in the S1‘ pocket for one of these inhibitors. |
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ISSN: | 0006-2960 1520-4995 |
DOI: | 10.1021/bi027045s |