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Protein Science, Vol 7, Issue 12 2483-2489, Copyright © 1998 by Cold Spring Harbor Laboratory Press

ARTICLE

Structural analysis of inhibitor binding to human carbonic anhydrase II

P. ANN-BORIACK-SJODIN, S. ZEITLIN, H. H. CHEN, L. CRENSHAW, S. GROSS, A. DANTANARAYANA, P. DELGADO, J. A. MAY, T. DEAN and D. W. CHRISTIANSON
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323 Current address: Biogen, Inc., 14 Cambridge Center, Cambridge, Massachusetts 02142.

X-ray crystal structures of carbonic anhydrase II (CAII) complexed with sulfonamide inhibitors illuminate the structural determinants of high affinity binding in the nanomolar regime. The primary binding interaction is the coordination of a primary sulfonamide group to the active site zinc ion. Secondary interactions fine-tune tight binding in regions of the active site cavity >5 A away from zinc, and this work highlights three such features: (1) advantageous conformational restraints of a bicyclic thienothiazene-6-sulfonamide-1,1-dioxide inhibitor skeleton in comparison with a monocyclic 2,5-thiophenedisulfonamide skeleton; (2) optimal substituents attached to a secondary sulfonamide group targeted to interact with hydrophobic patches defined by Phe131, Leu198, and Pro202; and (3) optimal stereochemistry and configuration at the C-4 position of bicyclic thienothiazene-6-sulfonamides; the C-4 substituent can interact with His64, the catalytic proton shuttle. Structure-activity relationships rationalize affinity trends observed during the development of brinzolamide (Azopt{TM}), the newest carbonic anhydrase inhibitor approved for the treatment of glaucoma.
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Home page
 Proc. Natl. Acad. Sci. USAHome page
D. A. Whittington, A. Waheed, B. Ulmasov, G. N. Shah, J. H. Grubb, W. S. Sly, and D. W. Christianson
Crystal structure of the dimeric extracellular domain of human carbonic anhydrase XII, a bitopic membrane protein overexpressed in certain cancer tumor cells
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[Abstract] [Full Text] [PDF]


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