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==Cryo-EM Structure of p110alpha in complex with p85alpha==
<StructureSection load='7myn' size='340' side='right'caption='[[7myn]], [[Resolution|resolution]] 2.79&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7myn]] 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=7MYN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MYN 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]] 2.79&#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=7myn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7myn OCA], [https://pdbe.org/7myn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7myn RCSB], [https://www.ebi.ac.uk/pdbsum/7myn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7myn ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/PK3CA_HUMAN PK3CA_HUMAN] Note=Most of the cancer-derived mutations are missense mutations and map to one of the three hotspots: Glu-542; Glu-545 and His-1047. Mutated isoforms participate in cellular transformation and tumorigenesis induced by oncogenic receptor tyrosine kinases (RTKs) and HRAS1/KRAS. Interaction with HRAS1/KRAS is required for Ras-driven tumor formation. Mutations increasing the lipid kinase activity are required for oncogenic signaling. The protein kinase activity may not be required for tumorigenesis.  Defects in PIK3CA are associated with colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500].  Defects in PIK3CA are a cause of susceptibility to breast cancer (BC) [MIM:[https://omim.org/entry/114480 114480]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case.  Defects in PIK3CA are a cause of susceptibility to ovarian cancer (OC) [MIM:[https://omim.org/entry/167000 167000]. Ovarian cancer common malignancy originating from ovarian tissue. Although many histologic types of ovarian neoplasms have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease.  Defects in PIK3CA may underlie hepatocellular carcinoma (HCC) [MIM:[https://omim.org/entry/114550 114550].<ref>PMID:15608678</ref>   Defects in PIK3CA are a cause of keratosis seborrheic (KERSEB) [MIM:[https://omim.org/entry/182000 182000]. A common benign skin tumor. Seborrheic keratoses usually begin with the appearance of one or more sharply defined, light brown, flat macules. The lesions may be sparse or numerous. As they initially grow, they develop a velvety to finely verrucous surface, followed by an uneven warty surface with multiple plugged follicles and a dull or lackluster appearance.<ref>PMID:17673550</ref>   Defects in PIK3CA are the cause of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE) [MIM:[https://omim.org/entry/612918 612918]. CLOVE is a sporadically occurring, non-hereditary disorder characterized by asymmetric somatic hypertrophy and anomalies in multiple organs. It is defined by four main clinical findings: congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/spinal abnormalities. The presence of truncal overgrowth and characteristic patterned macrodactyly at birth differentiates CLOVE from other syndromic forms of overgrowth.<ref>PMID:22658544</ref> 
== Function ==
[https://www.uniprot.org/uniprot/PK3CA_HUMAN PK3CA_HUMAN] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation in breast cancer cells through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Has also serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS.<ref>PMID:21708979</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Phosphoinositide 3-kinases (PI3Ks) are lipid kinases essential for growth and metabolism. Their aberrant activation is associated with many types of cancers. Here we used single-particle cryoelectron microscopy (cryo-EM) to determine three distinct conformations of full-length PI3Kalpha (p110alpha-p85alpha): the unliganded heterodimer PI3Kalpha, PI3Kalpha bound to the p110alpha-specific inhibitor BYL-719, and PI3Kalpha exposed to an activating phosphopeptide. The cryo-EM structures of unbound and of BYL-719-bound PI3Kalpha are in general accord with published crystal structures. Local deviations are presented and discussed. BYL-719 stabilizes the structure of PI3Kalpha, but three regions of low-resolution extra density remain and are provisionally assigned to the cSH2, BH, and SH3 domains of p85. One of the extra density regions is in contact with the kinase domain blocking access to the catalytic site. This conformational change indicates that the effects of BYL-719 on PI3Kalpha activity extend beyond competition with adenosine triphosphate (ATP). In unliganded PI3Kalpha, the DFG motif occurs in the "in" and "out" positions. In BYL-719-bound PI3Kalpha, only the DFG-in position, corresponding to the active conformation of the kinase, was observed. The phosphopeptide-bound structure of PI3Kalpha is composed of a stable core resolved at 3.8 A. It contains all p110alpha domains except the adaptor-binding domain (ABD). The p85alpha domains, linked to the core through the ABD, are no longer resolved, implying that the phosphopeptide activates PI3Kalpha by fully releasing the niSH2 domain from binding to p110alpha. The structures presented here show the basal form of the full-length PI3Kalpha dimer and document conformational changes related to the activated and inhibited states.

Cryo-EM structures of PI3Kalpha reveal conformational changes during inhibition and activation.,Liu X, Yang S, Hart JR, Xu Y, Zou X, Zhang H, Zhou Q, Xia T, Zhang Y, Yang D, Wang MW, Vogt PK Proc Natl Acad Sci U S A. 2021 Nov 9;118(45):e2109327118. doi: , 10.1073/pnas.2109327118. PMID:34725156<ref>PMID:34725156</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7myn" 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: Hart JR]]
[[Category: Liu X]]
[[Category: Vogt PK]]
[[Category: Wang M-W]]
[[Category: Xia T]]
[[Category: Xu Y]]
[[Category: Yang D]]
[[Category: Yang S]]
[[Category: Zhang H]]
[[Category: Zhang Y]]
[[Category: Zhou Q]]
[[Category: Zou X]]