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4rvt

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Revision as of 23:39, 21 October 2015

MAP4K4 in complex with a pyridin-2(1H)-one derivative

Structural highlights

4rvt is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

Function

[M4K4_HUMAN] Serine/threonine kinase that may play a role in the response to environmental stress and cytokines such as TNF-alpha. Appears to act upstream of the JUN N-terminal pathway. Phosphorylates SMAD1 on Thr-322.^[1] ^[2]

Publication Abstract from PubMed

Progressive loss and impaired restoration of neuronal activity are hallmarks of neurological diseases, and new small molecules with neurotrophic activity are in high demand. The militarinone alkaloids and structurally simplified analogues with 4-hydroxy-2-pyridone core structure induce pronounced neurite outgrowth, but their protein target has not been identified. Reported herein is the synthesis of a militarinone-inspired 4-hydroxy-2-pyridone collection, its investigation for enhancement of neurite outgrowth, and the discovery of the stress pathway kinase MAP4K4 as a target of the discovered neuritogenic pyridones. The most potent 4-hydroxy-2-pyridone is a selective ATP-competitive inhibitor of MAP4K4 but not of the other stress pathway related kinases, as proven by biochemical analysis and by a crystal structure of the inhibitor in complex with MAP4K4. The findings support the notion that MAP4K4 may be a new target for the treatment of neurodegenerative diseases.

Neuritogenic Militarinone-Inspired 4-Hydroxypyridones Target the Stress Pathway Kinase MAP4K4.,Schroder P, Forster T, Kleine S, Becker C, Richters A, Ziegler S, Rauh D, Kumar K, Waldmann H Angew Chem Int Ed Engl. 2015 Apr 23. doi: 10.1002/anie.201501515. PMID:25908259^[3]

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

References

↑ Yao Z, Zhou G, Wang XS, Brown A, Diener K, Gan H, Tan TH. A novel human STE20-related protein kinase, HGK, that specifically activates the c-Jun N-terminal kinase signaling pathway. J Biol Chem. 1999 Jan 22;274(4):2118-25. PMID:9890973
↑ Kaneko S, Chen X, Lu P, Yao X, Wright TG, Rajurkar M, Kariya K, Mao J, Ip YT, Xu L. Smad inhibition by the Ste20 kinase Misshapen. Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):11127-32. doi:, 10.1073/pnas.1104128108. Epub 2011 Jun 20. PMID:21690388 doi:http://dx.doi.org/10.1073/pnas.1104128108
↑ Schroder P, Forster T, Kleine S, Becker C, Richters A, Ziegler S, Rauh D, Kumar K, Waldmann H. Neuritogenic Militarinone-Inspired 4-Hydroxypyridones Target the Stress Pathway Kinase MAP4K4. Angew Chem Int Ed Engl. 2015 Apr 23. doi: 10.1002/anie.201501515. PMID:25908259 doi:http://dx.doi.org/10.1002/anie.201501515

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4rvt"

@@ Line 5: / Line 5: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3XM:3-HEXANOYL-4-HYDROXY-5-(4-HYDROXYPHENYL)PYRIDIN-2(1H)-ONE'>3XM</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene></td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
-<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=4rvt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rvt OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4rvt RCSB], [http://www.ebi.ac.uk/pdbsum/4rvt PDBsum]</span></td></tr>
+<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=4rvt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rvt OCA], [http://pdbe.org/4rvt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rvt RCSB], [http://www.ebi.ac.uk/pdbsum/4rvt PDBsum]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 17: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4rvt" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4rvt

From Proteopedia

Revision as of 23:39, 21 October 2015

MAP4K4 in complex with a pyridin-2(1H)-one derivative

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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