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4zk5

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Revision as of 06:51, 26 July 2016

MAP4K4 in complex with inhibitor GNE-495

Structural highlights

4zk5 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, ProSAT

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

Diverse biological roles for mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) have necessitated the identification of potent inhibitors in order to study its function in various disease contexts. In particular, compounds that can be used to carry out such studies in vivo would be critical for elucidating the potential for therapeutic intervention. A structure-based design effort coupled with property-guided optimization directed at minimizing the ability of the inhibitors to cross into the CNS led to an advanced compound 13 (GNE-495) that showed excellent potency and good PK and was used to demonstrate in vivo efficacy in a retinal angiogenesis model recapitulating effects that were observed in the inducible Map4k4 knockout mice.

Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis.,Ndubaku CO, Crawford TD, Chen H, Boggs JW, Drobnick J, Harris SF, Jesudason R, McNamara E, Nonomiya J, Sambrone A, Schmidt S, Smyczek T, Vitorino P, Wang L, Wu P, Yeung S, Chen J, Chen K, Ding CZ, Wang T, Xu Z, Gould SE, Murray LJ, Ye W ACS Med Chem Lett. 2015 Jun 29;6(8):913-8. doi: 10.1021/acsmedchemlett.5b00174., eCollection 2015 Aug 13. PMID:26288693^[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
↑ Ndubaku CO, Crawford TD, Chen H, Boggs JW, Drobnick J, Harris SF, Jesudason R, McNamara E, Nonomiya J, Sambrone A, Schmidt S, Smyczek T, Vitorino P, Wang L, Wu P, Yeung S, Chen J, Chen K, Ding CZ, Wang T, Xu Z, Gould SE, Murray LJ, Ye W. Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis. ACS Med Chem Lett. 2015 Jun 29;6(8):913-8. doi: 10.1021/acsmedchemlett.5b00174., eCollection 2015 Aug 13. PMID:26288693 doi:http://dx.doi.org/10.1021/acsmedchemlett.5b00174

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/4zk5"

@@ Line 1: / Line 1: @@
 ==MAP4K4 in complex with inhibitor GNE-495==
 <StructureSection load='4zk5' size='340' side='right' caption='[[4zk5]], [[Resolution|resolution]] 2.89&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4P4:8-AMINO-N-[1-(CYCLOPROPYLCARBONYL)AZETIDIN-3-YL]-2-(3-FLUOROPHENYL)-1,7-NAPHTHYRIDINE-5-CARBOXAMIDE'>4P4</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=4zk5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zk5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4zk5 RCSB], [http://www.ebi.ac.uk/pdbsum/4zk5 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=4zk5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zk5 OCA], [http://pdbe.org/4zk5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zk5 RCSB], [http://www.ebi.ac.uk/pdbsum/4zk5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zk5 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4zk5" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4zk5

From Proteopedia

Revision as of 06:51, 26 July 2016

MAP4K4 in complex with inhibitor GNE-495

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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