View source for 8ilv


==Cryo-EM structure of PI3Kalpha in complex with compound 18==
<StructureSection load='8ilv' size='340' side='right'caption='[[8ilv]], [[Resolution|resolution]] 3.19&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8ilv]] is a 2 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=8ILV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8ILV FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.19&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=L2V:N-[(2R)-1-(ethylamino)-1-oxidanylidene-3-[3-(2-quinoxalin-6-ylethynyl)phenyl]propan-2-yl]-2,3-dimethyl-quinoxaline-6-carboxamide'>L2V</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=8ilv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ilv OCA], [https://pdbe.org/8ilv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ilv RCSB], [https://www.ebi.ac.uk/pdbsum/8ilv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ilv ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/P85A_HUMAN P85A_HUMAN] Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling.<ref>PMID:7518429</ref> <ref>PMID:17626883</ref> <ref>PMID:19805105</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Class IA phosphoinositide 3-kinase alpha (PI3Kalpha) is an important drug target because it is one of the most frequently mutated proteins in human cancers. However, small molecule inhibitors currently on the market or under development have safety concerns due to a lack of selectivity. Therefore, other chemical scaffolds or unique mechanisms of catalytic kinase inhibition are needed. Here, we report the cryo-electron microscopy structures of wild-type PI3Kalpha, the dimer of p110alpha and p85alpha, in complex with three Y-shaped ligands [cpd16 (compound 16), cpd17 (compound 17), and cpd18 (compound 18)] of different affinities and no inhibitory effect on the kinase activity. Unlike ATP-competitive inhibitors, cpd17 adopts a Y-shaped conformation with one arm inserted into a binding pocket formed by R770 and W780 and the other arm lodged in the ATP-binding pocket at an angle that is different from that of the ATP phosphate tail. Such a special interaction induces a conformation of PI3Kalpha resembling that of the unliganded protein. These observations were confirmed with two isomers (cpd16 and cpd18). Further analysis of these Y-shaped ligands revealed the structural basis of differential binding affinities caused by stereo- or regiochemical modifications. Our results may offer a different direction toward the design of therapeutic agents against PI3Kalpha.

Structural insights into the interaction of three Y-shaped ligands with PI3Kalpha.,Zhou Q, Liu X, Neri D, Li W, Favalli N, Bassi G, Yang S, Yang D, Vogt PK, Wang MW Proc Natl Acad Sci U S A. 2023 Aug 22;120(34):e2304071120. doi: , 10.1073/pnas.2304071120. Epub 2023 Aug 16. PMID:37585458<ref>PMID:37585458</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8ilv" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bassi G]]
[[Category: Favalli N]]
[[Category: Li W]]
[[Category: Liu X]]
[[Category: Neri D]]
[[Category: Vogt PK]]
[[Category: Wang M-W]]
[[Category: Yang D]]
[[Category: Yang S]]
[[Category: Zhou Q]]