4RRW

Crystal Structure of Apo Murine Cyclooxygenase-2

4RRW の概要

• エントリーDOI: 10.2210/pdb4rrw/pdb
• 関連するPDBエントリー: 4RRX 4RRY 4RRZ 4RS0
• 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, ... (5 entities in total)
• 機能のキーワード: prostaglandin-endoperoxide synthase, glycosylation, membrane, oxidoreductase
• 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: 274165.24

構造登録者

Xu, S.,Blobaum, A.L.,Banerjee, S.,Marnett, L.J. (登録日: 2014-11-06, 公開日: 2015-04-08, 最終更新日: 2024-10-09)

主引用文献

Blobaum, A.L.,Xu, S.,Rowlinson, S.W.,Duggan, K.C.,Banerjee, S.,Kudalkar, S.N.,Birmingham, W.R.,Ghebreselasie, K.,Marnett, L.J.
Action at a Distance: MUTATIONS OF PERIPHERAL RESIDUES TRANSFORM RAPID REVERSIBLE INHIBITORS TO SLOW, TIGHT BINDERS OF CYCLOOXYGENASE-2.
J.Biol.Chem., 290:12793-12803, 2015

PubMed Abstract: Cyclooxygenase enzymes (COX-1 and COX-2) catalyze the conversion of arachidonic acid to prostaglandin G2. The inhibitory activity of rapid, reversible COX inhibitors (ibuprofen, naproxen, mefenamic acid, and lumiracoxib) demonstrated a significant increase in potency and time dependence of inhibition against double tryptophan murine COX-2 mutants at the 89/90 and 89/119 positions. In contrast, the slow, time-dependent COX inhibitors (diclofenac, indomethacin, and flurbiprofen) were unaffected by those mutations. Further mutagenesis studies suggested that mutation at position 89 was principally responsible for the changes in inhibitory potency of rapid, reversible inhibitors, whereas mutation at position 90 may exert some effect on the potency of COX-2-selective diarylheterocycle inhibitors; no effect was observed with mutation at position 119. Several crystal structures with or without NSAIDs indicated that placement of a bulky residue at position 89 caused a closure of a gap at the lobby, and alteration of histidine to tryptophan at position 90 changed the electrostatic profile of the side pocket of COX-2. Thus, these two residues, especially Val-89 at the lobby region, are crucial for the entrance and exit of some NSAIDs from the COX active site.

PubMed: 25825493
DOI: 10.1074/jbc.M114.635987

実験手法

X-RAY DIFFRACTION (2.569 Å)