title: 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 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.
authors.affiliation: Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Jude
authors.forename: Abir L
authors.initials: AL
authors.lastname: Banerjee
authors.forename: Manas K
authors.initials: MK
authors.lastname: Haldar
authors.forename: Sumathra
authors.initials: S
authors.lastname: Manokaran
authors.forename: Bidhan
authors.initials: B
authors.lastname: Roy
authors.forename: Sanku
authors.initials: S
authors.lastname: Mallik
authors.forename: D K
authors.initials: DK
authors.lastname: Srivastava
authors.forename: David W
authors.initials: DW
authors.lastname: Christianson
mesh_terms: D024401:Carbonic Anhydrase I / Q000737:chemistry* / Q000378:metabolism; D024402:Carbonic Anhydrase II / Q000737:chemistry* / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D003300:Copper / Q000737:chemistry; D018360:Crystallography, X-Ray; D006639:Histidine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007098:Imino Acids / Q000737:chemistry; D008958:Models, Molecular; D013449:Sulfonamides / Q000737:chemistry; D000096926:Benzenesulfonamides
chemical_list: D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; D002257:Carbonic Anhydrase Inhibitors; D003300:Copper; D006639:Histidine; D007098:Imino Acids; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C008109:iminodiacetic acid