View source for 6ykg


==Structure-based exploration of selectivity for ATM inhibitors in Huntingtons disease==
<StructureSection load='6ykg' size='340' side='right'caption='[[6ykg]], [[Resolution|resolution]] 3.12&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6ykg]] 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=6YKG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YKG 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]] 3.12&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OZ8:4-morpholin-4-yl-6-[(2~{R})-2-(phenylmethyl)pyrrolidin-1-yl]-1~{H}-pyridin-2-one'>OZ8</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=6ykg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ykg OCA], [https://pdbe.org/6ykg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ykg RCSB], [https://www.ebi.ac.uk/pdbsum/6ykg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ykg ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PK3C3_HUMAN PK3C3_HUMAN] Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate which plays a key role in initiation and maturation of autophagosomes. Involved in the transport of lysosomal enzyme precursors to lysosomes. Required for the abcission step in cytokinesis. Required for transport from early to late endosomes.<ref>PMID:7628435</ref> <ref>PMID:14617358</ref> <ref>PMID:20208530</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Our group has recently shown that brain-penetrant ataxia telangiectasia-mutated (ATM) kinase inhibitors may have potential as novel therapeutics for the treatment of Huntington's disease (HD). However, the previously described pyranone-thioxanthenes (e.g., 4) failed to afford selectivity over a vacuolar protein sorting 34 (Vps34) kinase, an important kinase involved with autophagy. Given that impaired autophagy has been proposed as a pathogenic mechanism of neurodegenerative diseases such as HD, achieving selectivity over Vps34 became an important objective for our program. Here, we report the successful selectivity optimization of ATM over Vps34 by using X-ray crystal structures of a Vps34-ATM protein chimera where the Vps34 ATP-binding site was mutated to approximate that of an ATM kinase. The morpholino-pyridone and morpholino-pyrimidinone series that resulted as a consequence of this selectivity optimization process have high ATM potency and good oral bioavailability and have lower molecular weight, reduced lipophilicity, higher aqueous solubility, and greater synthetic tractability compared to the pyranone-thioxanthenes.

Structure-Based Exploration of Selectivity for ATM Inhibitors in Huntington's Disease.,Van de Poel A, Toledo-Sherman L, Breccia P, Cachope R, Bate JR, Angulo-Herrera I, Wishart G, Matthews KL, Martin SL, Peacock M, Barnard A, Cox HC, Jones G, McAllister G, Vater H, Esmieu W, Clissold C, Lamers M, Leonard P, Jarvis RE, Blackaby W, Eznarriaga M, Lazari O, Yates D, Rose M, Jang SW, Munoz-Sanjuan I, Dominguez C J Med Chem. 2021 Mar 30. doi: 10.1021/acs.jmedchem.1c00114. PMID:33783225<ref>PMID:33783225</ref>

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

==See Also==
*[[Phosphoinositide 3-kinase 3D structures|Phosphoinositide 3-kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Lamers MBAC]]
[[Category: Leonard PM]]
[[Category: Van de Poel A]]