3U8H

Functionally selective inhibition of Group IIA phospholipase A2 reveals a role for vimentin in regulating arachidonic acid metabolism

3U8H の概要

• エントリーDOI: 10.2210/pdb3u8h/pdb
• 関連するPDBエントリー: 3U8B 3U8D 3U8I
• 分子名称: Phospholipase A2, membrane associated, (S)-5-(4-BENZYLOXY-PHENYL)-4-(7-PHENYL-HEPTANOYLAMINO)-PENTANOIC ACID, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: secreted phospholipase a2, phospholipase a2 activity, hydrolase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Peripheral membrane protein: P14555
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 29167.41

構造登録者

Lee, L.K.,Bryant, K.J.,Bouveret, R.,Lei, P.-W.,Duff, A.P.,Harrop, S.J.,Huang, E.P.,Harvey, R.P.,Gelb, M.H.,Gray, P.P.,Curmi, P.M.,Cunningham, A.M.,Church, W.B.,Scott, K.F. (登録日: 2011-10-17, 公開日: 2012-10-17, 最終更新日: 2024-10-30)

主引用文献

Lee, L.K.,Bryant, K.J.,Bouveret, R.,Lei, P.W.,Duff, A.P.,Harrop, S.J.,Huang, E.P.,Harvey, R.P.,Gelb, M.H.,Gray, P.P.,Curmi, P.M.,Cunningham, A.M.,Church, W.B.,Scott, K.F.
Selective Inhibition of Human Group IIA-secreted Phospholipase A2 (hGIIA) Signaling Reveals Arachidonic Acid Metabolism Is Associated with Colocalization of hGIIA to Vimentin in Rheumatoid Synoviocytes.
J.Biol.Chem., 288:15269-15279, 2013

PubMed Abstract: Human group IIA secreted phospholipase A2 (hGIIA) promotes tumor growth and inflammation and can act independently of its well described catalytic lipase activity via an alternative poorly understood signaling pathway. With six chemically diverse inhibitors we show that it is possible to selectively inhibit hGIIA signaling over catalysis, and x-ray crystal structures illustrate that signaling involves a pharmacologically distinct surface to the catalytic site. We demonstrate in rheumatoid fibroblast-like synoviocytes that non-catalytic signaling is associated with rapid internalization of the enzyme and colocalization with vimentin. Trafficking of exogenous hGIIA was monitored with immunofluorescence studies, which revealed that vimentin localization is disrupted by inhibitors of signaling that belong to a rare class of small molecule inhibitors that modulate protein-protein interactions. This study provides structural and pharmacological evidence for an association between vimentin, hGIIA, and arachidonic acid metabolism in synovial inflammation, avenues for selective interrogation of hGIIA signaling, and new strategies for therapeutic hGIIA inhibitor design.

PubMed: 23482564
DOI: 10.1074/jbc.M112.397893

実験手法

X-RAY DIFFRACTION (2.3 Å)