Ultrahigh resolution crystal structures of human carbonic anhydrases I and II complexed with "two-prong" inhibitors reveal the molecular basis of high affinity

    Authors

    K. M. Jude; A. L. Banerjee; M. K. Haldar; S. Manokaran; B. Roy; S. Mallik; D. K. Srivastava;D. W. Christianson

    Comments

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    Abbreviated Journal Title

    J. Am. Chem. Soc.

    Keywords

    ISOZYME-IX; AROMATIC SULFONAMIDES; SELECTIVE INHIBITORS; CATALYTIC; MECHANISM; BINDING CONSTANTS; DIFFRACTION DATA; METAL-COMPLEXES; DERIVATIVES; DESIGN; ZINC; Chemistry, Multidisciplinary

    Abstract

    The atomic-resolution crystal structures of human carbonic anhydrases I and I I complexed with "two-prong" inhibitors are reported. Each inhibitor contains a benzenesulfonamide prong and a cupric iminodiacetate (IDA-Cu2+) prong separated by linkers of different lengths and compositions. The ionized NH- group of each benzenesulfonamide coordinates to the active site Zn2+ ion; the IDA-Cu2+ prong of the tightest-binding inhibitor, BR30, binds to H64 of CAII and H200 of CAI. This work provides the first evidence verifying the structural basis of nanomolar affinity measured for two-prong inhibitors targeting the carbonic anhydrases.

    Journal Title

    Journal of the American Chemical Society

    Volume

    128

    Issue/Number

    9

    Publication Date

    1-1-2006

    Document Type

    Article

    Language

    English

    First Page

    3011

    Last Page

    3018

    WOS Identifier

    WOS:000235942000054

    ISSN

    0002-7863

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