2aw1

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spinqualitylabelsall models 2aw1, resolution 1.46Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Carbonic anhydrase inhibitors: Valdecoxib binds to a different active site region of the human isoform II as compared to the structurally related cyclooxygenase II "selective" inhibitor Celecoxib

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The high resolution X-ray crystal structure of the adduct of human, carbonic anhydrase (CA, EC 4.2.1.1) isoform II (hCA II) with the, clinically used painkiller valdecoxib, acting as a potent CA II and, cyclooxygenase-2 (COX-2) inhibitor, is reported. The ionized sulfonamide, moiety of valdecoxib is coordinated to the catalytic Zn(II) ion with a, tetrahedral geometry. The phenyl-isoxazole moiety of the inhibitor fills, the active site channel and interacts with the side chains of Gln92, Val121, Leu198, Thr200, and Pro202. Its 3-phenyl group is located into a, hydrophobic pocket, simultaneously establishing van der Waals interactions, with the aliphatic side chain of various hydrophobic residues (Val135, Ile91, Val121, Leu198, and Leu141) and a strong offset face-to-face, stacking interaction with the aromatic ring of Phe131 (the chi1 angle of, which is rotated about 90 degrees with respect to what was observed in the, structure of the native enzyme and those of other sulfonamide complexes)., Celecoxib, a structurally related COX-2 inhibitor for which the X-ray, crystal structure was reported earlier, binds in a completely different, manner to hCA II as compared to valdecoxib. Celecoxib completely fills the, entire CA II active site, with its trifluoromethyl group in the, hydrophobic part of the active site and the p-tolyl moiety in the, hydrophilic one, not establishing any interaction with Phe131. In contrast, to celecoxib, valdecoxib was rotated about 90 degrees around the chemical, bond connecting the benzensulfonamide and the substituted isoxazole ring, allowing for these multiple favorable interactions. These different, binding modes allow for the further drug design of various CA inhibitors, belonging to the benzenesulfonamide class.

Disease

Known disease associated with this structure: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis OMIM:[611492]

About this Structure

2AW1 is a Single protein structure of sequence from Homo sapiens with ZN, HGB, COX and GOL as ligands. Active as Carbonate dehydratase, with EC number 4.2.1.1 Full crystallographic information is available from OCA.

Reference

Carbonic anhydrase inhibitors: Valdecoxib binds to a different active site region of the human isoform II as compared to the structurally related cyclooxygenase II "selective" inhibitor celecoxib., Di Fiore A, Pedone C, D'Ambrosio K, Scozzafava A, De Simone G, Supuran CT, Bioorg Med Chem Lett. 2006 Jan 15;16(2):437-42. Epub 2005 Nov 14. PMID:16290146

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