6bl4

Crystal Complex of Cyclooxygenase-2 with indomethacin-ethylenediamine-dansyl conjugate

spinqualitylabelsall models 6bl4, resolution 2.22Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6bl4 is a 4 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: BOG, DXS, HEM, NAG Gene: Ptgs2, Cox-2, Cox2, Pghs-b, Tis10 (LK3 transgenic mice) Activity: Prostaglandin-endoperoxide synthase, with EC number 1.14.99.1 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 Many indomethacin amides and esters are cyclooxygenase-2- (COX-2)-selective inhibitors, providing a framework for the design of COX-2-targeted imaging and cancer chemotherapeutic agents. Although previous studies have suggested that the amide or ester moiety of these inhibitors binds in the lobby region, a spacious alcove within the enzyme's membrane-binding domain, structural details have been lacking. Here, we present observations on the crystal complexes of COX-2 with two indomethacin-dansyl conjugates (compounds 1and 2) at 2.22 A resolution. Both compounds are COX-2-selective inhibitors with IC50values of 0.76 muM and 0.17 muM, respectively. Our results confirmed that the dansyl moiety is localized in and establishes hydrophobic interactions and several hydrogen bonds with the lobby of the membrane binding domain. We noted that in both crystal structures, the linker tethering indomethacin to the dansyl moiety passes through the constriction at the mouth of the COX-2 active site, resulting in displacement and disorder of Arg-120, located at the opening to the active site. Both compounds exhibited higher inhibitory potency against a COX-2 R120A variant than against the wild-type enzyme. Inhibition kinetics of compound 2were similar to those of the indomethacin parent compound against wild-type COX-2, and the R120A substitution reduced the time dependency of COX inhibition. These results provide a structural basis for the further design and optimization of conjugated COX reagents for imaging of malignant or inflammatory tissues containing high COX-2 levels. Fluorescent indomethacin-dansyl conjugates utilize the membrane-binding domain of cyclooxygenase-2 to block the opening to the active site.,Xu S, Uddin MJ, Banerjee S, Duggan K, Musee J, Kiefer JR, Ghebreselasie K, Rouzer CA, Marnett LJ J Biol Chem. 2019 Apr 18. pii: RA119.007405. doi: 10.1074/jbc.RA119.007405. PMID:31000626 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cyclooxygenase 3D structures

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