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5byy

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ERK5 IN COMPLEX WITH SMALL MOLECULE

Structural highlights

5byy is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.79Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

MAP kinases act as an integration point for multiple biochemical signals and are involved in a wide variety of cellular processes such as proliferation, differentiation, regulation of transcription and development. As a member of the MAP kinase family, ERK5 (MAPK7) is involved in the downstream signalling pathways of various cell-surface receptors, including receptor tyrosine kinases and G protein-coupled receptors. In the current study, five structures of the ERK5 kinase domain co-crystallized with ERK5 inhibitors are reported. Interestingly, three of the compounds bind at a novel allosteric binding site in ERK5, while the other two bind at the typical ATP-binding site. Binding of inhibitors at the allosteric site is accompanied by displacement of the P-loop into the ATP-binding site and is shown to be ATP-competitive in an enzymatic assay of ERK5 kinase activity. Kinase selectivity data show that the most potent allosteric inhibitor exhibits superior kinase selectivity compared with the two inhibitors that bind at the canonical ATP-binding site. An analysis of these structures and comparison with both a previously published ERK5-inhibitor complex structure (PDB entry 4b99) and the structures of three other kinases (CDK2, ITK and MEK) in complex with allosteric inhibitors are presented.

Discovery of a novel allosteric inhibitor-binding site in ERK5: comparison with the canonical kinase hinge ATP-binding site.,Chen H, Tucker J, Wang X, Gavine PR, Phillips C, Augustin MA, Schreiner P, Steinbacher S, Preston M, Ogg D Acta Crystallogr D Struct Biol. 2016 May 1;72(Pt 5):682-93. doi:, 10.1107/S2059798316004502. Epub 2016 Apr 26. PMID:27139631^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Kato Y, Kravchenko VV, Tapping RI, Han J, Ulevitch RJ, Lee JD. BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C. EMBO J. 1997 Dec 1;16(23):7054-66. PMID:9384584 doi:10.1093/emboj/16.23.7054
↑ Kato Y, Tapping RI, Huang S, Watson MH, Ulevitch RJ, Lee JD. Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor. Nature. 1998 Oct 15;395(6703):713-6. PMID:9790194 doi:10.1038/27234
↑ Hayashi M, Tapping RI, Chao TH, Lo JF, King CC, Yang Y, Lee JD. BMK1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoid-inducible kinase. J Biol Chem. 2001 Mar 23;276(12):8631-4. Epub 2001 Jan 31. PMID:11254654 doi:10.1074/jbc.C000838200
↑ Dong F, Gutkind JS, Larner AC. Granulocyte colony-stimulating factor induces ERK5 activation, which is differentially regulated by protein-tyrosine kinases and protein kinase C. Regulation of cell proliferation and survival. J Biol Chem. 2001 Apr 6;276(14):10811-6. Epub 2001 Jan 17. PMID:11278431 doi:10.1074/jbc.M008748200
↑ Yang Q, Liao L, Deng X, Chen R, Gray NS, Yates JR 3rd, Lee JD. BMK1 is involved in the regulation of p53 through disrupting the PML-MDM2 interaction. Oncogene. 2012 Aug 6. doi: 10.1038/onc.2012.332. PMID:22869143 doi:10.1038/onc.2012.332
↑ Chen H, Tucker J, Wang X, Gavine PR, Phillips C, Augustin MA, Schreiner P, Steinbacher S, Preston M, Ogg D. Discovery of a novel allosteric inhibitor-binding site in ERK5: comparison with the canonical kinase hinge ATP-binding site. Acta Crystallogr D Struct Biol. 2016 May 1;72(Pt 5):682-93. doi:, 10.1107/S2059798316004502. Epub 2016 Apr 26. PMID:27139631 doi:http://dx.doi.org/10.1107/S2059798316004502

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5byy"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[5byy]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5BYY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5BYY FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4WG:2-{[2-ETHOXY-4-(4-HYDROXYPIPERIDIN-1-YL)PHENYL]AMINO}-5,11-DIMETHYL-5,11-DIHYDRO-6H-PYRIMIDO[4,5-B][1,4]BENZODIAZEPIN-6-ONE'>4WG</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.79&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4WG:2-{[2-ETHOXY-4-(4-HYDROXYPIPERIDIN-1-YL)PHENYL]AMINO}-5,11-DIMETHYL-5,11-DIHYDRO-6H-PYRIMIDO[4,5-B][1,4]BENZODIAZEPIN-6-ONE'>4WG</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=5byy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5byy OCA], [https://pdbe.org/5byy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5byy RCSB], [https://www.ebi.ac.uk/pdbsum/5byy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5byy ProSAT]</span></td></tr>
 </table>

5byy

From Proteopedia

Current revision

ERK5 IN COMPLEX WITH SMALL MOLECULE

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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