4b99

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{{STRUCTURE_4b99| PDB=4b99 | SCENE= }}
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==Crystal Structure of MAPK7 (ERK5) with inhibitor==
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===Crystal Structure of MAPK7 (ERK5) with inhibitor===
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<StructureSection load='4b99' size='340' side='right' caption='[[4b99]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
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{{ABSTRACT_PUBMED_23656407}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4b99]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B99 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4B99 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=R4L:11-CYCLOPENTYL-2-[[2-METHOXY-4-[4-(4-METHYLPIPERAZIN-1-YL)PIPERIDIN-1-YL]CARBONYL-PHENYL]AMINO]-5-METHYL-PYRIMIDO[4,5-B][1,4]BENZODIAZEPIN-6-ONE'>R4L</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4b99 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b99 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4b99 RCSB], [http://www.ebi.ac.uk/pdbsum/4b99 PDBsum]</span></td></tr>
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</table>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The protein kinase ERK5 (MAPK7) is an emerging drug target for a variety of indications, in particular for cancer where it plays a key role mediating cell proliferation, survival, epithelial-mesenchymal transition, and angiogenesis. To date, no three-dimensional structure has been published that would allow rational design of inhibitors. To address this, we determined the X-ray crystal structure of the human ERK5 kinase domain in complex with a highly specific benzo[e]pyrimido[5,4-b]diazepine-6(11H)-one inhibitor. The structure reveals that specific residue differences in the ATP-binding site, compared to the related ERKs p38s and JNKs, allow for the development of ERK5-specific inhibitors. The selectivity of previously observed ERK5 inhibitors can also be rationalized using this structure, which provides a template for future development of inhibitors with potential for treatment of disease.
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==Function==
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X-ray Crystal Structure of ERK5 (MAPK7) in Complex with a Specific Inhibitor.,Elkins JM, Wang J, Deng X, Pattison MJ, Arthur JS, Erazo T, Gomez N, Lizcano JM, Gray NS, Knapp S J Med Chem. 2013 Jun 13;56(11):4413-21. doi: 10.1021/jm4000837. Epub 2013 May 17. PMID:23656407<ref>PMID:23656407</ref>
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[[http://www.uniprot.org/uniprot/MK07_HUMAN MK07_HUMAN]] Plays a role in various cellular processes such as proliferation, differentiation and cell survival. The upstream activator of MAPK7 is the MAPK kinase MAP2K5. Upon activation, it translocates to the nucleus and phosphorylates various downstream targets including MEF2C. EGF activates MAPK7 through a Ras-independent and MAP2K5-dependent pathway. May have a role in muscle cell differentiation. May be important for endothelial function and maintenance of blood vessel integrity. MAP2K5 and MAPK7 interact specifically with one another and not with MEK1/ERK1 or MEK2/ERK2 pathways. Phosphorylates SGK1 at Ser-78 and this is required for growth factor-induced cell cycle progression. Involved in the regulation of p53/TP53 by disrupting the PML-MDM2 interaction.<ref>PMID:9384584</ref> <ref>PMID:9790194</ref> <ref>PMID:11254654</ref> <ref>PMID:11278431</ref> <ref>PMID:22869143</ref>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4b99]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B99 OCA].
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</div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:023656407</ref><references group="xtra"/><references/>
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*[[Mitogen-activated protein kinase|Mitogen-activated protein kinase]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Mitogen-activated protein kinase]]
[[Category: Mitogen-activated protein kinase]]
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[[Category: Arrowsmith, C.]]
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[[Category: Arrowsmith, C]]
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[[Category: Bountra, C.]]
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[[Category: Bountra, C]]
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[[Category: Delft, F Von.]]
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[[Category: Delft, F Von]]
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[[Category: Deng, X.]]
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[[Category: Deng, X]]
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[[Category: Edwards, A.]]
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[[Category: Edwards, A]]
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[[Category: Elkins, J M.]]
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[[Category: Elkins, J M]]
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[[Category: Gray, N S.]]
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[[Category: Gray, N S]]
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[[Category: Knapp, S.]]
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[[Category: Knapp, S]]
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[[Category: Mahajan, P.]]
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[[Category: Mahajan, P]]
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[[Category: Pike, A C.W.]]
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[[Category: Pike, A C.W]]
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[[Category: Savitsky, P.]]
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[[Category: Savitsky, P]]
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[[Category: Vollmar, M.]]
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[[Category: Vollmar, M]]
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[[Category: Wang, J.]]
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[[Category: Wang, J]]
[[Category: Inhibitor]]
[[Category: Inhibitor]]
[[Category: Transferase]]
[[Category: Transferase]]

Revision as of 10:09, 21 December 2014

Crystal Structure of MAPK7 (ERK5) with inhibitor

4b99, resolution 2.80Å

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