Ultrahigh Resolution Crystal Structures of Human Carbonic Anhydrases I and II Complexed with “Two-Prong” Inhibitors Reveal the Molecular Basis of High Affinity
Journal of the American Chemical Society2006Vol. 128(9), pp. 3011–3018
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Kevin M. Jude, Abir L. Banerjee, Manas K. Haldar, S. Manokaran, Bidhan C. Roy, Sanku Mallik, D. K. Srivastava, David W. Christianson
Abstract
The atomic-resolution crystal structures of human carbonic anhydrases I and II complexed with "two-prong" inhibitors are reported. Each inhibitor contains a benzenesulfonamide prong and a cupric iminodiacetate (IDA-Cu(2+)) prong separated by linkers of different lengths and compositions. The ionized NH(-) group of each benzenesulfonamide coordinates to the active site Zn(2+) ion; the IDA-Cu(2+) 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.
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