6yat: Difference between revisions
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==Crystal structure of STK4 (MST1) in complex with compound 6== | ==Crystal structure of STK4 (MST1) in complex with compound 6== | ||
<StructureSection load='6yat' size='340' side='right'caption='[[6yat]]' scene=''> | <StructureSection load='6yat' size='340' side='right'caption='[[6yat]], [[Resolution|resolution]] 2.58Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YAT OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6yat]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YAT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YAT FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3FX:(2R)-3-(CYCLOHEXYLAMINO)-2-HYDROXYPROPANE-1-SULFONIC+ACID'>3FX</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=OJ5:4-[5-(3-chlorophenyl)-7~{H}-pyrrolo[2,3-d]pyrimidin-4-yl]morpholine'>OJ5</scene></td></tr> | ||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">STK4, KRS2, MST1 ([https://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'>[https://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=6yat FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yat OCA], [https://pdbe.org/6yat PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yat RCSB], [https://www.ebi.ac.uk/pdbsum/6yat PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yat ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://www.uniprot.org/uniprot/STK4_HUMAN STK4_HUMAN]] Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. Key component of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. STK3/MST2 and STK4/MST1 are required to repress proliferation of mature hepatocytes, to prevent activation of facultative adult liver stem cells (oval cells), and to inhibit tumor formation (By similarity). Phosphorylates 'Ser-14' of histone H2B (H2BS14ph) during apoptosis. Phosphorylates FOXO3 upon oxidative stress, which results in its nuclear translocation and cell death initiation. Phosphorylates MOBKL1A, MOBKL1B and RASSF2. Phosphorylates TNNI3 (cardiac Tn-I) and alters its binding affinity to TNNC1 (cardiac Tn-C) and TNNT2 (cardiac Tn-T). Phosphorylates FOXO1 on 'Ser-212' and regulates its activation and stimulates transcription of PMAIP1 in a FOXO1-dependent manner. Phosphorylates SIRT1 and inhibits SIRT1-mediated p53/TP53 deacetylation, thereby promoting p53/TP53 dependent transcription and apoptosis upon DNA damage. Acts as an inhibitor of PKB/AKT1. Phosphorylates AR on 'Ser-650' and suppresses its activity by intersecting with PKB/AKT1 signaling and antagonizing formation of AR-chromatin complexes.<ref>PMID:8816758</ref> <ref>PMID:8702870</ref> <ref>PMID:11278283</ref> <ref>PMID:11517310</ref> <ref>PMID:12757711</ref> <ref>PMID:15109305</ref> <ref>PMID:16510573</ref> <ref>PMID:16751106</ref> <ref>PMID:16930133</ref> <ref>PMID:17932490</ref> <ref>PMID:18328708</ref> <ref>PMID:18986304</ref> <ref>PMID:19525978</ref> <ref>PMID:21245099</ref> <ref>PMID:21512132</ref> <ref>PMID:21212262</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Serine/threonine-protein kinases 3 and 4 (STK3 and STK4, respectively) are key components of the Hippo signaling pathway, which regulates cell proliferation and death and provides a potential therapeutic target for acute myeloid leukemia (AML). Herein, we report the structure-based design of a series of pyrrolopyrimidine derivatives as STK3 and STK4 inhibitors. In an initial screen, the compounds exhibited low nanomolar potency against both STK3 and STK4. Crystallization of compound 6 with STK4 revealed two-point hinge binding in the ATP-binding pocket. Further characterization and analysis demonstrated that compound 20 (SBP-3264) specifically inhibited the Hippo signaling pathway in cultured mammalian cells and possessed favorable pharmacokinetic and pharmacodynamic properties in mice. We show that genetic knockdown and pharmacological inhibition of STK3 and STK4 suppress the proliferation of AML cells in vitro. Thus, SBP-3264 is a valuable chemical probe for understanding the roles of STK3 and STK4 in AML and is a promising candidate for further advancement as a potential therapy. | |||
Inhibitors of the Hippo Pathway Kinases STK3/MST2 and STK4/MST1 Have Utility for the Treatment of Acute Myeloid Leukemia.,Bata N, Chaikuad A, Bakas NA, Limpert AS, Lambert LJ, Sheffler DJ, Berger LM, Liu G, Yuan C, Wang L, Peng Y, Dong J, Celeridad M, Layng F, Knapp S, Cosford NDP J Med Chem. 2021 Nov 22. doi: 10.1021/acs.jmedchem.1c00804. PMID:34807584<ref>PMID:34807584</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6yat" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Bakas | [[Category: Non-specific serine/threonine protein kinase]] | ||
[[Category: Bata N]] | [[Category: Bakas, N A]] | ||
[[Category: Chaikuad A]] | [[Category: Bata, N]] | ||
[[Category: Cosford | [[Category: Chaikuad, A]] | ||
[[Category: Knapp S]] | [[Category: Cosford, N D.P]] | ||
[[Category: Lambert | [[Category: Knapp, S]] | ||
[[Category: Limpert | [[Category: Lambert, L J]] | ||
[[Category: Limpert, A S]] | |||
[[Category: Structural genomic]] | |||
[[Category: Chemical probe]] | |||
[[Category: Hippo pathway]] | |||
[[Category: Kinase]] | |||
[[Category: Kinase inhibitor]] | |||
[[Category: Mst1]] | |||
[[Category: Sgc]] | |||
[[Category: Stk4]] | |||
[[Category: Transferase]] | |||