4M10

Crystal Structure of Murine Cyclooxygenase-2 Complex with Isoxicam

4M10 の概要

• エントリーDOI: 10.2210/pdb4m10/pdb
• 関連するPDBエントリー: 4M11
• 分子名称: Prostaglandin G/H synthase 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• 機能のキーワード: nsaid, cox, dioxygenase, peroxidase, glycosylation, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Mus musculus (mouse)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 277774.88

構造登録者

Xu, S.,Hermanson, D.J.,Banerjee, S.,Ghebreelasie, K.,Marnett, L.J. (登録日: 2013-08-02, 公開日: 2014-01-22, 最終更新日: 2024-11-20)

主引用文献

Xu, S.,Hermanson, D.J.,Banerjee, S.,Ghebreselasie, K.,Clayton, G.M.,Garavito, R.M.,Marnett, L.J.
Oxicams Bind in a Novel Mode to the Cyclooxygenase Active Site via a Two-water-mediated H-bonding Network.
J.Biol.Chem., 289:6799-6808, 2014

PubMed Abstract: Oxicams are widely used nonsteroidal anti-inflammatory drugs (NSAIDs), but little is known about the molecular basis of the interaction with their target enzymes, the cyclooxygenases (COX). Isoxicam is a nonselective inhibitor of COX-1 and COX-2 whereas meloxicam displays some selectivity for COX-2. Here we report crystal complexes of COX-2 with isoxicam and meloxicam at 2.0 and 2.45 angstroms, respectively, and a crystal complex of COX-1 with meloxicam at 2.4 angstroms. These structures reveal that the oxicams bind to the active site of COX-2 using a binding pose not seen with other NSAIDs through two highly coordinated water molecules. The 4-hydroxyl group on the thiazine ring partners with Ser-530 via hydrogen bonding, and the heteroatom of the carboxamide ring of the oxicam scaffold interacts with Tyr-385 and Ser-530 through a highly coordinated water molecule. The nitrogen atom of the thiazine and the oxygen atom of the carboxamide bind to Arg-120 and Tyr-355 via another highly ordered water molecule. The rotation of Leu-531 in the structure opens a novel binding pocket, which is not utilized for the binding of other NSAIDs. In addition, a detailed study of meloxicam·COX-2 interactions revealed that mutation of Val-434 to Ile significantly reduces inhibition by meloxicam due to subtle changes around Phe-518, giving rise to the preferential inhibition of COX-2 over COX-1.

PubMed: 24425867
DOI: 10.1074/jbc.M113.517987

実験手法

X-RAY DIFFRACTION (2.01 Å)