6bl3: Difference between revisions
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==Crystal Complex of Cyclooxygenase-2 with indomethacin-butyldiamine-dansyl conjugate== | |||
<StructureSection load='6bl3' size='340' side='right'caption='[[6bl3]], [[Resolution|resolution]] 2.22Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6bl3]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BL3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6BL3 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.217Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=L7M:2-[1-(4-chlorophenyl)carbonyl-5-methoxy-2-methyl-indol-3-yl]-~{N}-[4-[[5-(dimethylamino)naphthalen-1-yl]sulfonylamino]butyl]ethanamide'>L7M</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6bl3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bl3 OCA], [https://pdbe.org/6bl3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6bl3 RCSB], [https://www.ebi.ac.uk/pdbsum/6bl3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6bl3 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/PGH2_MOUSE 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.<ref>PMID:12925531</ref> <ref>PMID:20463020</ref> <ref>PMID:20810665</ref> <ref>PMID:21489986</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:31000626</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6bl3" style="background-color:#fffaf0;"></div> | ||
[[Category: Banerjee | |||
[[Category: | ==See Also== | ||
[[Category: | *[[Cyclooxygenase 3D structures|Cyclooxygenase 3D structures]] | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mus musculus]] | |||
[[Category: Banerjee S]] | |||
[[Category: Marnett LJ]] | |||
[[Category: Uddin MJ]] | |||
[[Category: Xu S]] | |||