High-resolution structure of human carbonic anhydrase II complexed with acetazolamide reveals insights into inhibitor drug design.
The crystal structure of human carbonic anhydrase II (CA II) complexed with the inhibitor acetazolamide (AZM) has been determined at 1.1 A resolution and refined to an R(cryst) of 11.2% and an R(free) of 14.7%. As observed in previous CA II-inhibitor complexes, AZM binds directly to the zinc and makes several key interactions with active-site residues. The high-resolution data also showed a glycerol molecule adjacent to the AZM in the active site and two additional AZMs that are adventitiously bound on the surface of the enzyme. The co-binding of AZM and glycerol in the active site demonstrate that given an appropriate ring orientation and substituents, an isozyme-specific CA inhibitor may be developed.
Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Katherine H
KH
Sippel
Arthur H
AH
Robbins
John
J
Domsic
Caroli
C
Genis
Mavis
M
Agbandje-McKenna
Robert
R
McKenna
D000086:Acetazolamide / Q000737:chemistry*; D024402:Carbonic Anhydrase II / Q000737:chemistry*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry*; D020134:Catalytic Domain / Q000187:drug effects*; D015195:Drug Design; D005990:Glycerol / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular
D002257:Carbonic Anhydrase Inhibitors; D024402:Carbonic Anhydrase II; D000086:Acetazolamide; D005990:Glycerol