Ultrahigh Resolution Crystal Structures Of Human Carbonic Anhydrases I And Ii Complexed With Two-Prong Inhibitors Reveal The Molecular Basis Of High Affinity

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 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. © 2006 American Chemical Society