4m10

Crystal Structure of Murine Cyclooxygenase-2 Complex with Isoxicam

spinqualitylabelsall models 4m10, resolution 2.01Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4m10 is a 4 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.01Å Ligands: BOG, HEM, ICD, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PGH2_MOUSE Mediates the formation of prostaglandins from arachidonate. May have a role as a major mediator of inflammation and/or a role for prostanoid signaling in activity-dependent plasticity. Publication Abstract from PubMed Oxicams are widely used non-steroidal 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 non-selective 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 angstroms 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. Oxicams Bind in a Novel Mode to the Cyclooxygenase Active Site via a Two-water-mediated H-bonding Network.,Xu S, Hermanson DJ, Banerjee S, Ghebreselasie K, Clayton GM, Garavito RM, Marnett LJ J Biol Chem. 2014 Jan 14. PMID:24425867 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cyclooxygenase 3D structures

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