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Broad-Spectrum Allosteric Inhibition of Herpesvirus Proteases

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      Abstract

      Herpesviruses rely on a homodimeric protease for viral capsid maturation. A small molecule, DD2, previously shown to disrupt dimerization of Kaposi’s sarcoma-associated herpesvirus protease (KSHV Pr) by trapping an inactive monomeric conformation and two analogues generated through carboxylate bioisosteric replacement (compounds 2 and 3) were shown to inhibit the associated proteases of all three human herpesvirus (HHV) subfamilies (α, β, and γ). Inhibition data reveal that compound 2 has potency comparable to or better than that of DD2 against the tested proteases. Nuclear magnetic resonance spectroscopy and a new application of the kinetic analysis developed by Zhang and Poorman [Zhang, Z. Y., Poorman, R. A., et al. (1991) J. Biol. Chem. 266, 15591–15594] show DD2, compound 2, and compound 3 inhibit HHV proteases by dimer disruption. All three compounds bind the dimer interface of other HHV proteases in a manner analogous to binding of DD2 to KSHV protease. The determination and analysis of cocrystal structures of both analogues with the KSHV Pr monomer verify and elaborate on the mode of binding for this chemical scaffold, explaining a newly observed critical structure–activity relationship. These results reveal a prototypical chemical scaffold for broad-spectrum allosteric inhibition of human herpesvirus proteases and an approach for the identification of small molecules that allosterically regulate protein activity by targeting protein–protein interactions.

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      Most cited references 42

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          The role of crystal packing in determining the observed conformations of amino acid side-chains in protein crystals is investigated by (1) analysis of a database of proteins that have been crystallized in different unit cells (space group or unit cell dimensions) and (2) theoretical predictions of side-chain conformations with the crystal environment explicitly represented. Both of these approaches indicate that the crystal environment plays an important role in determining the conformations of polar side-chains on the surfaces of proteins. Inclusion of the crystal environment permits a more sensitive measurement of the achievable accuracy of side-chain prediction programs, when validating against structures obtained by X-ray crystallography. Our side-chain prediction program uses an all-atom force field and a Generalized Born model of solvation and is thus capable of modeling simple packing effects (i.e. van der Waals interactions), electrostatic effects, and desolvation, which are all important mechanisms by which the crystal environment impacts observed side-chain conformations. Our results are also relevant to the understanding of changes in side-chain conformation that may result from ligand docking and protein-protein association, insofar as the results reveal how side-chain conformations change in response to their local environment. (c) 2002 Elsevier Science Ltd.
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            Author and article information

            Affiliations
            []Department of Pharmaceutical Chemistry, University of California , San Francisco, California 94158-2280, United States
            []Small Molecule Discovery Center, University of California , San Francisco, California 94158-2250, United States
            [§ ]Graduate Group in Biochemistry and Molecular Biology, University of California , San Francisco, California 94158-2280, United States
            []Department of Biochemistry and Biophysics, University of California , San Francisco, California 94158-2280, United States
            Author notes
            [* ]E-mail: charles.craik@ 123456ucsf.edu . Phone: (415) 476-8146.
            Journal
            Biochemistry
            Biochemistry
            bi
            bichaw
            Biochemistry
            American Chemical Society
            0006-2960
            1520-4995
            30 June 2015
            30 June 2014
            22 July 2014
            : 53
            : 28
            : 4648-4660
            24977643 4108181 10.1021/bi5003234
            Copyright © 2014 American Chemical Society

            Terms of Use

            Funding
            National Institutes of Health, United States
            Categories
            Article
            Custom metadata
            bi5003234
            bi-2014-003234

            Biochemistry

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