4u43: Difference between revisions

Revision as of 08:00, 22 March 2023

MAP4K4 in complex with inhibitor (compound 6)

Structural highlights

4u43 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:	3D8
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

MAP4K4 has been shown to regulate key cellular processes that are tied to disease pathogenesis. In an effort to generate small molecule MAP4K4 inhibitors, a fragment-based screen was carried out and a pyrrolotriazine fragment with excellent ligand efficiency was identified. Further modification of this fragment guided by X-ray crystal structures and molecular modeling led to the discovery of a series of promising compounds with good structural diversity and physicochemical properties. These compounds exhibited single digit nanomolar potency and compounds 35 and 44 achieved good in vivo exposure.

Fragment-based identification and optimization of a class of potent pyrrolo[2,1-f][1,2,4]triazine MAP4K4 inhibitors.,Wang L, Stanley M, Boggs JW, Crawford TD, Bravo BJ, Giannetti AM, Harris SF, Magnuson SR, Nonomiya J, Schmidt S, Wu P, Ye W, Gould SE, Murray LJ, Ndubaku CO, Chen H Bioorg Med Chem Lett. 2014 Aug 2. pii: S0960-894X(14)00795-1. doi:, 10.1016/j.bmcl.2014.07.071. PMID:25139565^[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
↑ Wang L, Stanley M, Boggs JW, Crawford TD, Bravo BJ, Giannetti AM, Harris SF, Magnuson SR, Nonomiya J, Schmidt S, Wu P, Ye W, Gould SE, Murray LJ, Ndubaku CO, Chen H. Fragment-based identification and optimization of a class of potent pyrrolo[2,1-f][1,2,4]triazine MAP4K4 inhibitors. Bioorg Med Chem Lett. 2014 Aug 2. pii: S0960-894X(14)00795-1. doi:, 10.1016/j.bmcl.2014.07.071. PMID:25139565 doi:https://dx.doi.org/10.1016/j.bmcl.2014.07.071

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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] Wang L, Stanley M, Boggs JW, Crawford TD, Bravo BJ, Giannetti AM, Harris SF, Magnuson SR, Nonomiya J, Schmidt S, Wu P, Ye W, Gould SE, Murray LJ, Ndubaku CO, Chen H. Fragment-based identification and optimization of a class of potent pyrrolo[2,1-f][1,2,4]triazine MAP4K4 inhibitors. Bioorg Med Chem Lett. 2014 Aug 2. pii: S0960-894X(14)00795-1. doi:, 10.1016/j.bmcl.2014.07.071. PMID:25139565 doi:https://dx.doi.org/10.1016/j.bmcl.2014.07.071

[1]

[2]

[3]

@@ Line 1: / Line 1: @@
 ==MAP4K4 in complex with inhibitor (compound 6)==
-<StructureSection load='4u43' size='340' side='right' caption='[[4u43]], [[Resolution|resolution]] 2.18&Aring;' scene=''>
+<StructureSection load='4u43' size='340' side='right'caption='[[4u43]], [[Resolution|resolution]] 2.18&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4u43]] 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=4U43 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4U43 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4u43]] 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=4U43 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4U43 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3D8:N-(PYRIDIN-3-YL)PYRROLO[2,1-F][1,2,4]TRIAZIN-4-AMINE'>3D8</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3D8:N-(PYRIDIN-3-YL)PYRROLO[2,1-F][1,2,4]TRIAZIN-4-AMINE'>3D8</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4u3y|4u3y]], [[4u3z|4u3z]], [[4u40|4u40]], [[4u41|4u41]], [[4u42|4u42]], [[4u44|4u44]], [[4u45|4u45]]</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=4u43 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4u43 OCA], [https://pdbe.org/4u43 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4u43 RCSB], [https://www.ebi.ac.uk/pdbsum/4u43 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4u43 ProSAT]</span></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MAP4K4, HGK, KIAA0687, NIK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4u43 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4u43 OCA], [http://pdbe.org/4u43 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4u43 RCSB], [http://www.ebi.ac.uk/pdbsum/4u43 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4u43 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 25: / Line 22: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Non-specific serine/threonine protein kinase]]
+[[Category: Large Structures]]
-[[Category: Coons, M]]
+[[Category: Coons M]]
-[[Category: Harris, S F]]
+[[Category: Harris SF]]
-[[Category: Wu, P]]
+[[Category: Wu P]]
-[[Category: Kinase]]
-[[Category: Transferase-transferase inhibitor complex]]

4u43: Difference between revisions

Revision as of 08:00, 22 March 2023

MAP4K4 in complex with inhibitor (compound 6)

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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