View source for 6s75


==Crystal structure of Nek7 bound to compound 51==
<StructureSection load='6s75' size='340' side='right'caption='[[6s75]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6s75]] is a 4 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=6S75 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6S75 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]] 3.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=F9N:3-[[6-(cyclohexylmethoxy)-7~{H}-purin-2-yl]amino]-~{N}-[3-(dimethylamino)propyl]benzenesulfonamide'>F9N</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=6s75 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6s75 OCA], [https://pdbe.org/6s75 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6s75 RCSB], [https://www.ebi.ac.uk/pdbsum/6s75 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6s75 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/NEK7_HUMAN NEK7_HUMAN] Protein kinase which plays an important role in mitotic cell cycle progression. Required for microtubule nucleation activity of the centrosome, robust mitotic spindle formation and cytokinesis. Phosphorylates RPS6KB1.<ref>PMID:17101132</ref> <ref>PMID:17586473</ref> <ref>PMID:19414596</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Nek7 is a serine/threonine-protein kinase required for proper spindle formation and cytokinesis. Elevated Nek7 levels have been observed in several cancers, and inhibition of Nek7 might provide a route to the development of cancer therapeutics. To date, no selective and potent Nek7 inhibitors have been identified. Nek7 crystal structures exhibit an improperly formed regulatory-spine (R-spine), characteristic of an inactive kinase. We reasoned that the preference of Nek7 to crystallise in this inactive conformation might hinder attempts to capture Nek7 in complex with Type I inhibitors. Here, we have introduced aromatic residues into the R-spine of Nek7 with the aim to stabilise the active conformation of the kinase through R-spine stacking. The strong R-spine mutant Nek7SRS retained catalytic activity and was crystallised in complex with compound 51, an ATP-competitive inhibitor of Nek2 and Nek7. Subsequently, we obtained the same crystal form for wild-type Nek7WT in apo form and bound to compound 51. The R-spines of the three well-ordered Nek7WT molecules exhibit variable conformations while the R-spines of the Nek7SRS molecules all have the same, partially stacked configuration. Compound 51 bound to Nek2 and Nek7 in similar modes, but differences in the precise orientation of a substituent highlights features that could be exploited in designing inhibitors that are selective for particular Nek family members. Although the SRS mutations are not required to obtain a Nek7-inhibitor structure, we conclude that it is a useful strategy for restraining the conformation of a kinase in order to promote crystallogenesis.

Nek7 conformational flexibility and inhibitor binding probed through protein engineering of the R-spine.,Byrne MJ, Nasir N, Basmadjian C, Bhatia C, Cunnison RF, Carr KH, Mas-Droux C, Yeoh S, Cano C, Bayliss R Biochem J. 2020 Apr 30;477(8):1525-1539. doi: 10.1042/BCJ20200128. PMID:32242624<ref>PMID:32242624</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6s75" style="background-color:#fffaf0;"></div>

==See Also==
*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bayliss R]]
[[Category: Nasir N]]