2AW1

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

2AW1 の概要

• エントリーDOI: 10.2210/pdb2aw1/pdb
• 関連するPDBエントリー: 1CA2 1OQ5
• 分子名称: Carbonic anhydrase II, ZINC ION, 4-(HYDROXYMERCURY)BENZOIC ACID, ... (6 entities in total)
• 機能のキーワード: carbonic anhydrase, protein-inhibitor complex, lyase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P00918
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 30060.53

構造登録者

Di Fiore, A.,Pedone, C.,D'Ambrosio, K.,Scozzafava, A.,De Simone, G.,Supuran, C.T. (登録日: 2005-08-31, 公開日: 2006-07-04, 最終更新日: 2023-10-25)

主引用文献

Di Fiore, A.,Pedone, C.,D'Ambrosio, K.,Scozzafava, A.,De Simone, G.,Supuran, C.T.
Carbonic anhydrase inhibitors: Valdecoxib binds to a different active site region of the human isoform II as compared to the structurally related cyclooxygenase II
Bioorg.Med.Chem.Lett., 16:437-442, 2006

PubMed Abstract: 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.

PubMed: 16290146
DOI: 10.1016/j.bmcl.2005.09.040

実験手法

X-RAY DIFFRACTION (1.46 Å)