1PXX

CRYSTAL STRUCTURE OF DICLOFENAC BOUND TO THE CYCLOOXYGENASE ACTIVE SITE OF COX-2

1PXX の概要

• エントリーDOI: 10.2210/pdb1pxx/pdb
• 関連するPDBエントリー: 1CVU 6COX
• 関連するBIRD辞書のPRD_ID: PRD_900017
• 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-(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: cox-2, cyclooxygenase, prostaglandin, diclofenac, endoperoxide, oxidoreductase
• 由来する生物種: Mus musculus (house mouse)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 284886.98

構造登録者

Kiefer, J.R.,Rowlinson, S.W.,Prusakiewicz, J.J.,Pawlitz, J.L.,Kozak, K.R.,Kalgutkar, A.S.,Stallings, W.C.,Marnett, L.J.,Kurumbail, R.G. (登録日: 2003-07-07, 公開日: 2003-09-09, 最終更新日: 2024-11-20)

主引用文献

Rowlinson, S.W.,Kiefer, J.R.,Prusakiewicz, J.J.,Pawlitz, J.L.,Kozak, K.R.,Kalgutkar, A.S.,Stallings, W.C.,Kurumbail, R.G.,Marnett, L.J.
A Novel Mechanism of Cyclooxygenase-2 Inhibition Involving Interactions with Ser-530 and Tyr-385.
J.Biol.Chem., 278:45763-45769, 2003

PubMed Abstract: A variety of drugs inhibit the conversion of arachidonic acid to prostaglandin G2 by the cyclooxygenase (COX) activity of prostaglandin endoperoxide synthases. Several modes of inhibitor binding in the COX active site have been described including ion pairing of carboxylic acid containing inhibitors with Arg-120 of COX-1 and COX-2 and insertion of arylsulfonamides and sulfones into the COX-2 side pocket. Recent crystallographic evidence suggests that Tyr-385 and Ser-530 chelate polar or negatively charged groups in arachidonic acid and aspirin. We tested the generality of this binding mode by analyzing the action of a series of COX inhibitors against site-directed mutants of COX-2 bearing changes in Arg-120, Tyr-355, Tyr-348, and Ser-530. Interestingly, diclofenac inhibition was unaffected by the mutation of Arg-120 to alanine but was dramatically attenuated by the S530A mutation. Determination of the crystal structure of a complex of diclofenac with murine COX-2 demonstrates that diclofenac binds to COX-2 in an inverted conformation with its carboxylate group hydrogen-bonded to Tyr-385 and Ser-530. This finding represents the first experimental demonstration that the carboxylate group of an acidic non-steroidal anti-inflammatory drug can bind to a COX enzyme in an orientation that precludes the formation of a salt bridge with Arg-120. Mutagenesis experiments suggest Ser-530 is also important in time-dependent inhibition by nimesulide and piroxicam.

PubMed: 12925531
DOI: 10.1074/jbc.M305481200

実験手法

X-RAY DIFFRACTION (2.9 Å)