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

J Am Chem Soc. 2006 Mar 8;128(9):3011-8. doi: 10.1021/ja057257n.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Benzenesulfonamides
  • Carbonic Anhydrase I / chemistry*
  • Carbonic Anhydrase I / metabolism
  • Carbonic Anhydrase II / chemistry*
  • Carbonic Anhydrase II / metabolism
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Carbonic Anhydrase Inhibitors / metabolism
  • Carbonic Anhydrase Inhibitors / pharmacology
  • Copper / chemistry
  • Crystallography, X-Ray
  • Histidine / chemistry
  • Histidine / metabolism
  • Humans
  • Imino Acids / chemistry
  • Models, Molecular
  • Sulfonamides / chemistry

Substances

  • Carbonic Anhydrase Inhibitors
  • Imino Acids
  • Sulfonamides
  • Histidine
  • Copper
  • Carbonic Anhydrase I
  • Carbonic Anhydrase II
  • iminodiacetic acid