View source for 9vfo


==Crystal Structure of the NUAK1-MARK3 kinase domain chimera bound with small molecule inhibitor 2-amino-N-(5-((5-chloro-4-(((3R,3aR,6R,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl)oxy)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acetamide==
<StructureSection load='9vfo' size='340' side='right'caption='[[9vfo]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9vfo]] 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=9VFO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9VFO 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]] 2.500106&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1ER0:~{N}-[5-[[4-[[(3~{R},3~{a}~{R},6~{R},6~{a}~{R})-3-methoxy-2,3,3~{a},5,6,6~{a}-hexahydrofuro[3,2-b]furan-6-yl]oxy]-5-chloranyl-pyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methyl-amino]phenyl]-2-azanyl-ethanamide'>A1ER0</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=9vfo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9vfo OCA], [https://pdbe.org/9vfo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9vfo RCSB], [https://www.ebi.ac.uk/pdbsum/9vfo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9vfo ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/MARK3_HUMAN MARK3_HUMAN] Involved in the specific phosphorylation of microtubule-associated proteins for tau, MAP2 and MAP4. Phosphorylates CDC25C on 'Ser-216'. Regulates localization and activity of some histone deacetylases by mediating phosphorylation of HDAC7, promoting subsequent interaction between HDAC7 and 14-3-3 and export from the nucleus.<ref>PMID:16980613</ref> 
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== Publication Abstract from PubMed ==
NUAK1, an AMPK-related kinase overexpressed in cancers, plays a crucial role in tumor metastasis and cell survival, making it an attractive cancer therapeutic target. Herein, we report potent, selective NUAK1 inhibitors via structure-guided repurposing of a covalent JAK3 inhibitor. By capitalizing on the critical structural difference horizontal line Cys909 in JAK3 versus Glu139 in NUAK1 horizontal line we substituted the electrophilic warhead with glutamate-favoring moieties, a modification that confers selective NUAK1 targeting. Supporting this design rationale, cocrystal structures verify the specific engagement of these moieties with the Glu139 residue of NUAK1. Among the synthesized analogs, candidate compound 10i exhibits subnanomolar NUAK1 inhibition (IC(50) = 0.49 nM) and kinome-wide selectivity. Besides, 10i suppresses proliferation, migration, and invasion of triple-negative breast cancer cells, reverses EMT markers, and shows robust antitumor efficacy in mouse xenografts. This study provides a promising lead and validates Glu139 as an anchor for selective NUAK1 targeting.

Structure-Based Design of Potent and Highly Selective NUAK1 Inhibitors by Exploiting a Unique Glutamate Switch for the Prevention of Tumor Growth, Migration, and Invasion.,Li S, Wang Y, Liu X, Zhang H, Lei C, Wang Z, Zhang Y, Du X, Xu L, Li Z, Shi Y, Ning X, Cao J, Zhang ZM, Ma D, Ding K J Med Chem. 2026 Apr 9;69(7):7817-7838. doi: 10.1021/acs.jmedchem.5c03079. Epub , 2026 Mar 19. PMID:41855469<ref>PMID:41855469</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 9vfo" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Zhang H]]
[[Category: Zhang ZM]]