5sxa

From Proteopedia

(Difference between revisions)

Current revision

Crystal Structure of PI3Kalpha in complex with fragment 10

Structural highlights

5sxa is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.35Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2] ^[3]

Publication Abstract from PubMed

PIK3CA, the gene that encodes the catalytic subunit of phosphatidylinositol 3-kinase alpha (PI3Kalpha), is frequently mutated in breast and other types of cancer. A specific inhibitor that targets the mutant forms of PI3Kalpha could maximize treatment efficiency while minimizing side-effects. Herein we describe the identification of novel binding pockets that may provide an opportunity for the design of mutant selective inhibitors. Using a fragment-based approach, we screened a library of 352 fragments (MW<300Da) for binding to PI3Kalpha by X-ray crystallography. Five novel binding pockets were identified, each providing potential opportunities for inhibitor design. Of particular interest was a binding pocket near Glu542, which is located in one of the two most frequently mutated domains.

Identification of allosteric binding sites for PI3Kalpha oncogenic mutant specific inhibitor design.,Miller MS, Maheshwari S, McRobb FM, Kinzler KW, Amzel LM, Vogelstein B, Gabelli SB Bioorg Med Chem. 2017 Feb 15;25(4):1481-1486. doi: 10.1016/j.bmc.2017.01.012., Epub 2017 Jan 16. PMID:28129991^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Vainikka S, Joukov V, Wennstrom S, Bergman M, Pelicci PG, Alitalo K. Signal transduction by fibroblast growth factor receptor-4 (FGFR-4). Comparison with FGFR-1. J Biol Chem. 1994 Jul 15;269(28):18320-6. PMID:7518429
↑ Miled N, Yan Y, Hon WC, Perisic O, Zvelebil M, Inbar Y, Schneidman-Duhovny D, Wolfson HJ, Backer JM, Williams RL. Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science. 2007 Jul 13;317(5835):239-42. PMID:17626883 doi:317/5835/239
↑ Mandelker D, Gabelli SB, Schmidt-Kittler O, Zhu J, Cheong I, Huang CH, Kinzler KW, Vogelstein B, Amzel LM. A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane. Proc Natl Acad Sci U S A. 2009 Oct 6;106(40):16996-7001. Epub 2009 Sep 23. PMID:19805105
↑ Miller MS, Maheshwari S, McRobb FM, Kinzler KW, Amzel LM, Vogelstein B, Gabelli SB. Identification of allosteric binding sites for PI3Kalpha oncogenic mutant specific inhibitor design. Bioorg Med Chem. 2017 Feb 15;25(4):1481-1486. doi: 10.1016/j.bmc.2017.01.012., Epub 2017 Jan 16. PMID:28129991 doi:http://dx.doi.org/10.1016/j.bmc.2017.01.012

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5sxa"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5sxa is ON HOLD  until Paper Publication
+==Crystal Structure of PI3Kalpha in complex with fragment 10==
+<StructureSection load='5sxa' size='340' side='right'caption='[[5sxa]], [[Resolution|resolution]] 3.35&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5sxa]] 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=5SXA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5SXA 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]] 3.35&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=71N:2-(TRIFLUOROMETHYL)-1H-BENZIMIDAZOL-5-AMINE'>71N</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</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=5sxa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5sxa OCA], [https://pdbe.org/5sxa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5sxa RCSB], [https://www.ebi.ac.uk/pdbsum/5sxa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5sxa 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 ==
+PIK3CA, the gene that encodes the catalytic subunit of phosphatidylinositol 3-kinase alpha (PI3Kalpha), is frequently mutated in breast and other types of cancer. A specific inhibitor that targets the mutant forms of PI3Kalpha could maximize treatment efficiency while minimizing side-effects. Herein we describe the identification of novel binding pockets that may provide an opportunity for the design of mutant selective inhibitors. Using a fragment-based approach, we screened a library of 352 fragments (MW&lt;300Da) for binding to PI3Kalpha by X-ray crystallography. Five novel binding pockets were identified, each providing potential opportunities for inhibitor design. Of particular interest was a binding pocket near Glu542, which is located in one of the two most frequently mutated domains.
-Authors:
+Identification of allosteric binding sites for PI3Kalpha oncogenic mutant specific inhibitor design.,Miller MS, Maheshwari S, McRobb FM, Kinzler KW, Amzel LM, Vogelstein B, Gabelli SB Bioorg Med Chem. 2017 Feb 15;25(4):1481-1486. doi: 10.1016/j.bmc.2017.01.012., Epub 2017 Jan 16. PMID:28129991<ref>PMID:28129991</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 5sxa" 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: Amzel LM]]
+[[Category: Gabelli SB]]
+[[Category: Miller MS]]
+[[Category: Vogelstein B]]

5sxa

From Proteopedia

Current revision

Crystal Structure of PI3Kalpha in complex with fragment 10

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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