8qlq: Difference between revisions
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The | ==Human MST3 (STK24) kinase in complex with macrocyclic inhibitor JA310== | ||
<StructureSection load='8qlq' size='340' side='right'caption='[[8qlq]], [[Resolution|resolution]] 1.64Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8qlq]] is a 1 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=8QLQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8QLQ FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.64Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=VY0:macrocyclic+inhibitor'>VY0</scene></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=8qlq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8qlq OCA], [https://pdbe.org/8qlq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8qlq RCSB], [https://www.ebi.ac.uk/pdbsum/8qlq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8qlq ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/STK24_HUMAN STK24_HUMAN] Serine/threonine-protein kinase that acts on both serine and threonine residues and promotes apoptosis in response to stress stimuli and caspase activation. Mediates oxidative-stress-induced cell death by modulating phosphorylation of JNK1-JNK2 (MAPK8 and MAPK9), p38 (MAPK11, MAPK12, MAPK13 and MAPK14) during oxidative stress. Plays a role in a staurosporine-induced caspase-independent apoptotic pathway by regulating the nuclear translocation of AIFM1 and ENDOG and the DNase activity associated with ENDOG. Phosphorylates STK38L on 'Thr-442' and stimulates its kinase activity. Regulates cellular migration with alteration of PTPN12 activity and PXN phosphorylation: phosphorylates PTPN12 and inhibits its activity and may regulate PXN phosphorylation through PTPN12. May act as a key regulator of axon regeneration in the optic nerve and radial nerve.<ref>PMID:16314523</ref> <ref>PMID:17046825</ref> <ref>PMID:19604147</ref> <ref>PMID:19855390</ref> <ref>PMID:19782762</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
MST1, MST2, MST3, MST4, and YSK1 are conserved members of the mammalian sterile 20-like serine/threonine (MST) family that regulate cellular functions such as proliferation and migration. The MST3 isozyme plays a role in regulating cell growth and apoptosis, and its dysregulation has been linked to high-grade tumors. To date, there are no isoform-selective inhibitors that could be used for validating the role of MST3 in tumorigenesis. We designed a series of 3-aminopyrazole-based macrocycles based on the structure of a promiscuous inhibitor. By varying the moieties targeting the solvent-exposed region and optimizing the linker, macrocycle JA310 (21c) was synthesized. JA310 exhibited high cellular potency for MST3 (EC(50) = 106 nM) and excellent kinome-wide selectivity. The crystal structure of the MST3-JA310 complex provided intriguing insights into the binding mode, which is associated with large-scale structural rearrangements. In summary, JA310 demonstrates the utility of macrocyclization for the design of highly selective inhibitors and presents the first chemical probe for MST3. | |||
Synthesis of Pyrazole-Based Macrocycles Leads to a Highly Selective Inhibitor for MST3.,Amrhein JA, Berger LM, Balourdas DI, Joerger AC, Menge A, Kramer A, Frischkorn JM, Berger BT, Elson L, Kaiser A, Schubert-Zsilavecz M, Muller S, Knapp S, Hanke T J Med Chem. 2024 Jan 11;67(1):674-690. doi: 10.1021/acs.jmedchem.3c01980. Epub , 2023 Dec 21. PMID:38126712<ref>PMID:38126712</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 8qlq" style="background-color:#fffaf0;"></div> | ||
[[Category: Amrhein | |||
[[Category: | ==See Also== | ||
[[Category: Hanke | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] | ||
[[Category: | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Amrhein JA]] | |||
[[Category: Balourdas DI]] | |||
[[Category: Hanke T]] | |||
[[Category: Joerger AC]] | |||
[[Category: Knapp S]] | |||