Ultrahigh Resolution Crystal Structures of Human CarbonicAnhydrases I and II Complexed with “Two-Prong” InhibitorsReveal the Molecular Basis of High Affinity
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 cupriciminodiacetate (IDA-Cu2+) prong separated by linkers of different lengths and compositions. The ionizedNH- group of each benzenesulfonamide coordinates to the active site Zn2+ ion; the IDA-Cu2+ prong of thetightest-binding inhibitor, BR30, binds to H64 of CAII and H200 of CAI. This work provides the first evidenceverifying the structural basis of nanomolar affinity measured for two-prong inhibitors targeting the carbonicanhydrases.
