View source for 4otj


==The complex of murine cyclooxygenase-2 with a conjugate of indomefathin and podophyllotoxin, N-{(succinylpodophyllotoxinyl)but-4-yl}-2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamide==
<StructureSection load='4otj' size='340' side='right'caption='[[4otj]], [[Resolution|resolution]] 2.11&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4otj]] 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=4OTJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OTJ 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]] 2.11&#8491;</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=IXP:(5S,5AS,8AS,9S)-8-OXO-9-(3,4,5-TRIMETHOXYPHENYL)-5,5A,6,8,8A,9-HEXAHYDROFURO[3,4 6,7]NAPHTHO[2,3-D][1,3]DIOXOL-5-YL+4-{[4-({[1-(4-CHLOROBENZOYL)-5-METHOXY-2-METHYL-1H-INDOL-3-YL]ACETYL}AMINO)BUTYL]AMINO}-4-OXOBUTANOATE'>IXP</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=4otj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4otj OCA], [https://pdbe.org/4otj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4otj RCSB], [https://www.ebi.ac.uk/pdbsum/4otj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4otj 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 ==
Targeted delivery of chemotherapeutic agents to tumors has been explored as a means to increase the selectivity and potency of cytotoxicity. Most efforts in this area have exploited the molecular recognition of proteins highly expressed on the surface of cancer cells followed by internalization. A related approach that has received less attention is the targeting of intracellular proteins by ligands conjugated to anticancer drugs. An attractive target for this approach is the enzyme cyclooxygenase-2 (COX-2), which is highly expressed in a range of malignant tumors. Herein, we describe the synthesis and evaluation of a series of chemotherapeutic agents targeted to COX-2 by conjugation to indomethacin. Detailed characterization of compound 12, a conjugate of indomethacin with podophyllotoxin, revealed highly potent and selective COX-2 inhibition in vitro and in intact cells. Kinetics and X-ray crystallographic studies demonstrated that compound 12 is a slow, tight-binding inhibitor that likely binds to COX-2's allosteric site with its indomethacin moiety in a conformation similar to that of indomethacin. Compound 12 exhibited cytotoxicity in cell culture similar to that of podophyllotoxin with no evidence of COX-2-dependent selectivity. However, in vivo, compound 12 accumulated selectively in and more effectively inhibited the growth of a COX-2-expressing xenograft compared to a xenograft that did not express COX-2. Compound 12, which we have named chemocoxib A, provides proof-of-concept for the in vivo targeting of chemotherapeutic agents to COX-2 but suggests that COX-2-dependent selectivity may not be evident in cell culture-based assays.

Antitumor Activity of Cytotoxic Cyclooxygenase-2 Inhibitors.,Uddin MJ, Crews BC, Xu S, Ghebreselasie K, Daniel CK, Kingsley PJ, Banerjee S, Marnett LJ ACS Chem Biol. 2016 Sep 19. PMID:27588346<ref>PMID:27588346</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4otj" style="background-color:#fffaf0;"></div>

==See Also==
*[[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]]