9wgw: Difference between revisions
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New page: '''Unreleased structure''' The entry 9wgw is ON HOLD Authors: Seo, J.H., Cheon, S.W. Description: human Dual specificity mitogen-activated protein kinase kinase 2 [[Category: Unrelease... |
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==Crystal structure of human Haspin with ATP-mimicking inhibitor LJ-4827== | |||
<StructureSection load='9wgw' size='340' side='right'caption='[[9wgw]], [[Resolution|resolution]] 2.70Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[9wgw]] 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=9WGW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9WGW 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]] 2.7Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1MBI:(2~{R},3~{R},4~{S},5~{R})-2-(4-azanyl-5-ethynyl-pyrrolo[2,3-d]pyrimidin-7-yl)-5-[[(azanylidene-$l^{4}-azanylidene)amino]methyl]thiolane-3,4-diol'>A1MBI</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=9wgw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9wgw OCA], [https://pdbe.org/9wgw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9wgw RCSB], [https://www.ebi.ac.uk/pdbsum/9wgw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9wgw ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/HASP_HUMAN HASP_HUMAN] Serine/threonine-protein kinase that phosphorylates histone H3 at 'Ser-3' (H3T3ph) during mitosis. This positions and activates AURKB and other components of the chromosomal passenger complex (CPC) at centromeres to ensure proper chromatid cohesion, metaphase alignment and normal progression through the cell cycle.<ref>PMID:11228240</ref> <ref>PMID:15681610</ref> <ref>PMID:17084365</ref> <ref>PMID:20705812</ref> <ref>PMID:20929775</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Despite genetic perturbations resulting in embryo lethality for most mitotic kinases, loss of the histone H3 mitotic kinase HASPIN reveals no adverse effect in mice models, establishing HASPIN as a promising target for anticancer therapy. However, developing a HASPIN inhibitor from conventional pharmacophores poses a technical challenge as this atypical kinase shares slight similarities with eukaryotic protein kinases. Chemically modifying a cytotoxic 4'-thioadenosine analogue through high genotoxicity yielded several novel nongenotoxic kinase inhibitors. In silico apporoaches utilizing transcriptomic and chemical similarities with known compounds and KINOMEscan profiles unveiled the HASPIN inhibitor LJ4827. LJ4827's specificity and potency as a HASPIN inhibitor were verified through in vitro kinase assay and X-ray crystallography. HASPIN inhibition by LJ4827 reduced histone H3 phosphorylation and impeded Aurora B recruitment in cancer cell centromeres but not in noncancer cells. Through transcriptome analysis of lung cancer patients, PLK1 was determined as a druggable synergistic partner to complement HASPIN inhibition. Chemical or genetic PLK1 perturbation with LJ4827 effectuated pronounced lung cancer cytotoxicity in vitro and in vivo. Therefore, LJ4827 is a novel anticancer therapeutic for selectively impeding cancer mitosis through potent HASPIN inhibition, and simultaneous HASPIN and PLK1 interference is a promising therapeutic strategy for lung cancer. | |||
In Silico Discovery of 5'-Modified 7-Deoxy-7-ethynyl-4'-thioadenosine as a HASPIN Inhibitor and Its Synergistic Anticancer Effect with the PLK1 Inhibitor.,Kwon EJ, Mashelkar KK, Seo J, Shin YZ, Sung K, Jang SC, Cheon SW, Lee H, Lee HW, Kim G, Han BW, Lee SK, Jeong LS, Cha HJ ACS Cent Sci. 2023 May 11;9(6):1140-1149. doi: 10.1021/acscentsci.3c00332. , eCollection 2023 Jun 28. PMID:37396870<ref>PMID:37396870</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Cheon | <div class="pdbe-citations 9wgw" style="background-color:#fffaf0;"></div> | ||
[[Category: Seo | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Cheon SW]] | |||
[[Category: Seo JH]] | |||
