View source for 8zul


==Crystal Structure of Human Myt1 Kinase domain Bounded with compound 8m==
<StructureSection load='8zul' size='340' side='right'caption='[[8zul]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8zul]] 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=8ZUL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8ZUL 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]] 1.8002616&#8491;</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=8zul FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8zul OCA], [https://pdbe.org/8zul PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8zul RCSB], [https://www.ebi.ac.uk/pdbsum/8zul PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8zul ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PMYT1_HUMAN PMYT1_HUMAN] Acts as a negative regulator of entry into mitosis (G2 to M transition) by phosphorylation of the CDK1 kinase specifically when CDK1 is complexed to cyclins. Mediates phosphorylation of CDK1 predominantly on 'Thr-14'. Also involved in Golgi fragmentation. May be involved in phosphorylation of CDK1 on 'Tyr-15' to a lesser degree, however tyrosine kinase activity is unclear and may be indirect. May be a downstream target of Notch signaling pathway during eye development.<ref>PMID:9001210</ref> <ref>PMID:10373560</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
CCNE1 amplification occurs in breast cancer and currently lacks effective therapies. PKMYT1 as a synthetic lethal target for CCNE1 amplification holds promise for the treatment of CCNE1-amplified breast cancer. Herein, we discover a series of 2-amino-[1,1'-biphenyl]-3-carboxamide derivatives as potent and selective PKMYT1 inhibitors using structure-based drug design. The representative compound 8ma exhibited excellent potency against PKMYT1, while sparing WEE1. It also suppressed proliferation of the CCNE1-amplified HCC1569 breast cancer cell line and showed synergistic cytotoxicity in combination with gemcitabine. PKMYT1 X-ray cocrystallography confirmed that introduction of key binding interactions between the inhibitors and residues Asp251 and Tyr121 of PKMYT1 greatly enhanced the potency and selectivity of the compounds.

Structure-Based Drug Design of 2-Amino-[1,1'-biphenyl]-3-carboxamide Derivatives as Selective PKMYT1 Inhibitors for the Treatment of CCNE1-Amplified Breast Cancer.,Wang C, Fang Y, Zhou Z, Liu Z, Feng F, Wan X, Li Y, Liu S, Ding J, Zhang ZM, Xie H, Lu X J Med Chem. 2024 Aug 20. doi: 10.1021/acs.jmedchem.4c01458. PMID:39163619<ref>PMID:39163619</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8zul" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Zhang ZM]]
[[Category: Zhou ZQ]]