4rvt: Difference between revisions

Revision as of 08:30, 8 March 2023

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

Structural highlights

4rvt is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	3XM, MES
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

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:https://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:https://dx.doi.org/10.1002/anie.201501515

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OCA

[1] 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

[2] 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:https://dx.doi.org/10.1073/pnas.1104128108

[3] 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:https://dx.doi.org/10.1002/anie.201501515

[1]

[2]

[3]

@@ Line 3: / Line 3: @@
 <StructureSection load='4rvt' size='340' side='right'caption='[[4rvt]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4rvt]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RVT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RVT FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4rvt]] 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=4RVT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RVT FirstGlance]. <br>
-</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>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HGK, KIAA0687, MAP4K4, NIK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4rvt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rvt OCA], [https://pdbe.org/4rvt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rvt RCSB], [https://www.ebi.ac.uk/pdbsum/4rvt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rvt ProSAT]</span></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://pdbe.org/4rvt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rvt RCSB], [http://www.ebi.ac.uk/pdbsum/4rvt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4rvt ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[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>
+[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>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 24: / Line 22: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Non-specific serine/threonine protein kinase]]
+[[Category: Becker C]]
-[[Category: Becker, C]]
+[[Category: Kleine S]]
-[[Category: Kleine, S]]
+[[Category: Rauh D]]
-[[Category: Rauh, D]]
+[[Category: Richters A]]
-[[Category: Richters, A]]
-[[Category: Dfg-in]]
-[[Category: Serine/threonine kinase]]
-[[Category: Transferase-transferase inhibitor complex]]
-[[Category: Type i]]

4rvt: Difference between revisions

Revision as of 08:30, 8 March 2023

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

Structural highlights

Function

Publication Abstract from PubMed

References

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