3u8d | pdb_00003u8d

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

spinqualitylabelsall models 3u8d, resolution 1.81Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3u8d is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CA, CL, U8D Related: 3u8b, 3u8h, 3u8i Gene: PLA2G2A, PLA2B, PLA2L, RASF-A (Homo sapiens) Activity: Phospholipase A(2), with EC number 3.1.1.4 Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed 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. 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.,Lee LK, Bryant KJ, Bouveret R, Lei PW, Duff AP, Harrop SJ, Huang EP, Harvey RP, Gelb MH, Gray PP, Curmi PM, Cunningham AM, Church WB, Scott KF J Biol Chem. 2013 May 24;288(21):15269-79. doi: 10.1074/jbc.M112.397893. Epub, 2013 Mar 12. PMID:23482564 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phospholipase A2

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