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4zk5

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==MAP4K4 in complex with inhibitor GNE-495==
==MAP4K4 in complex with inhibitor GNE-495==
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<StructureSection load='4zk5' size='340' side='right' caption='[[4zk5]], [[Resolution|resolution]] 2.89&Aring;' scene=''>
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<StructureSection load='4zk5' size='340' side='right'caption='[[4zk5]], [[Resolution|resolution]] 2.89&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4zk5]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZK5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ZK5 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4zk5]] is a 2 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=4ZK5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZK5 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=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>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.89&#8491;</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/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>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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>
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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=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>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4zk5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zk5 OCA], [https://pdbe.org/4zk5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zk5 RCSB], [https://www.ebi.ac.uk/pdbsum/4zk5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zk5 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/M4K4_HUMAN 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.<ref>PMID:9890973</ref> <ref>PMID:21690388</ref>
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[https://www.uniprot.org/uniprot/M4K4_HUMAN 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.<ref>PMID:9890973</ref> <ref>PMID:21690388</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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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<ref>PMID:26288693</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Homo sapiens]]
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[[Category: Coons, M]]
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[[Category: Large Structures]]
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[[Category: Harris, S F]]
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[[Category: Coons M]]
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[[Category: Wu, P]]
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[[Category: Harris SF]]
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[[Category: Kinase]]
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[[Category: Wu P]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

MAP4K4 in complex with inhibitor GNE-495

PDB ID 4zk5

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