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4b99

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Crystal Structure of MAPK7 (ERK5) with inhibitor

Structural highlights

4b99 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 2.8Å
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

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.

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^[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
↑ Elkins JM, Wang J, Deng X, Pattison MJ, Arthur JS, Erazo T, Gomez N, Lizcano JM, Gray NS, Knapp S. X-ray Crystal Structure of ERK5 (MAPK7) in Complex with a Specific Inhibitor. J Med Chem. 2013 Jun 13;56(11):4413-21. doi: 10.1021/jm4000837. Epub 2013 May 17. PMID:23656407 doi:10.1021/jm4000837

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/4b99"

@@ Line 3: / Line 3: @@
 <StructureSection load='4b99' size='340' side='right'caption='[[4b99]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4b99]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. 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 [https://proteopedia.org/fgij/fg.htm?mol=4B99 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4b99]] 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=4B99 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4B99 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] </span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4b99 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b99 OCA], [https://pdbe.org/4b99 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4b99 RCSB], [https://www.ebi.ac.uk/pdbsum/4b99 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4b99 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://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>
+[https://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>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 26: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Mitogen-activated protein kinase]]
+[[Category: Arrowsmith C]]
-[[Category: Arrowsmith, C]]
+[[Category: Bountra C]]
-[[Category: Bountra, C]]
+[[Category: Deng X]]
-[[Category: Delft, F von]]
+[[Category: Edwards A]]
-[[Category: Deng, X]]
+[[Category: Elkins JM]]
-[[Category: Edwards, A]]
+[[Category: Gray NS]]
-[[Category: Elkins, J M]]
+[[Category: Knapp S]]
-[[Category: Gray, N S]]
+[[Category: Mahajan P]]
-[[Category: Knapp, S]]
+[[Category: Pike ACW]]
-[[Category: Mahajan, P]]
+[[Category: Savitsky P]]
-[[Category: Pike, A C.W]]
+[[Category: Vollmar M]]
-[[Category: Savitsky, P]]
+[[Category: Wang J]]
-[[Category: Vollmar, M]]
+[[Category: Von Delft F]]
-[[Category: Wang, J]]
-[[Category: Inhibitor]]
-[[Category: Transferase]]

4b99

From Proteopedia

Current revision

Crystal Structure of MAPK7 (ERK5) with inhibitor

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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