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Open data
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Basic information
Entry | Database: PDB / ID: 8ts7 | ||||||
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Title | Human PI3K p85alpha/p110alpha | ||||||
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![]() | SIGNALING PROTEIN / Lipid kinase | ||||||
Function / homology | ![]() perinuclear endoplasmic reticulum membrane / response to muscle inactivity / negative regulation of actin filament depolymerization / regulation of toll-like receptor 4 signaling pathway / response to L-leucine / phosphatidylinositol kinase activity / regulation of actin filament organization / response to butyrate / phosphatidylinositol 3-kinase regulator activity / IRS-mediated signalling ...perinuclear endoplasmic reticulum membrane / response to muscle inactivity / negative regulation of actin filament depolymerization / regulation of toll-like receptor 4 signaling pathway / response to L-leucine / phosphatidylinositol kinase activity / regulation of actin filament organization / response to butyrate / phosphatidylinositol 3-kinase regulator activity / IRS-mediated signalling / cellular response to hydrostatic pressure / autosome genomic imprinting / positive regulation of focal adhesion disassembly / phosphatidylinositol 3-kinase activator activity / interleukin-18-mediated signaling pathway / PI3K events in ERBB4 signaling / myeloid leukocyte migration / 1-phosphatidylinositol-3-kinase regulator activity / phosphatidylinositol 3-kinase regulatory subunit binding / neurotrophin TRKA receptor binding / Activated NTRK2 signals through PI3K / positive regulation of protein localization to membrane / Activated NTRK3 signals through PI3K / cis-Golgi network / ErbB-3 class receptor binding / negative regulation of fibroblast apoptotic process / kinase activator activity / phosphatidylinositol 3-kinase complex, class IB / vasculature development / transmembrane receptor protein tyrosine kinase adaptor activity / RHOF GTPase cycle / RHOD GTPase cycle / Signaling by cytosolic FGFR1 fusion mutants / regulation of cellular respiration / positive regulation of endoplasmic reticulum unfolded protein response / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IA / enzyme-substrate adaptor activity / anoikis / phosphatidylinositol 3-kinase complex / Nephrin family interactions / Signaling by LTK in cancer / RND1 GTPase cycle / relaxation of cardiac muscle / Costimulation by the CD28 family / Signaling by LTK / positive regulation of leukocyte migration / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / MET activates PI3K/AKT signaling / RND2 GTPase cycle / PI3K/AKT activation / positive regulation of filopodium assembly / RND3 GTPase cycle / phosphatidylinositol-4,5-bisphosphate 3-kinase / vascular endothelial growth factor signaling pathway / negative regulation of stress fiber assembly / growth hormone receptor signaling pathway / phosphatidylinositol 3-kinase / natural killer cell mediated cytotoxicity / insulin binding / phosphatidylinositol-3-phosphate biosynthetic process / RHOV GTPase cycle / negative regulation of macroautophagy / 1-phosphatidylinositol-3-kinase activity / Signaling by ALK / negative regulation of cell-matrix adhesion / RHOB GTPase cycle / GP1b-IX-V activation signalling / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / PI-3K cascade:FGFR2 / protein kinase activator activity / response to dexamethasone / PI-3K cascade:FGFR4 / RHOC GTPase cycle / RHOJ GTPase cycle / PI-3K cascade:FGFR1 / negative regulation of osteoclast differentiation / intracellular glucose homeostasis / CD28 dependent PI3K/Akt signaling / Synthesis of PIPs at the plasma membrane / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / CDC42 GTPase cycle / RHOU GTPase cycle / PI3K events in ERBB2 signaling / negative regulation of anoikis / intercalated disc / RET signaling / T cell differentiation / Interleukin-3, Interleukin-5 and GM-CSF signaling / insulin receptor substrate binding / RHOG GTPase cycle / extrinsic apoptotic signaling pathway via death domain receptors / regulation of multicellular organism growth / PI3K Cascade / RHOA GTPase cycle / endothelial cell migration / positive regulation of TOR signaling Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ![]() ![]() ![]() | ||||||
![]() | Holliday, M. / Tang, Y. / Bulku, A. / Wilbur, J. / Fraser, J. | ||||||
Funding support | 1items
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![]() | ![]() Title: Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia. Authors: Andreas Varkaris / Ermira Pazolli / Hakan Gunaydin / Qi Wang / Levi Pierce / Alessandro A Boezio / Artemisa Bulku / Lucian DiPietro / Cary Fridrich / Adam Frost / Fabrizio Giordanetto / ...Authors: Andreas Varkaris / Ermira Pazolli / Hakan Gunaydin / Qi Wang / Levi Pierce / Alessandro A Boezio / Artemisa Bulku / Lucian DiPietro / Cary Fridrich / Adam Frost / Fabrizio Giordanetto / Erika P Hamilton / Katherine Harris / Michael Holliday / Tamieka L Hunter / Amanda Iskandar / Yongli Ji / Alexandre Larivée / Jonathan R LaRochelle / André Lescarbeau / Fabien Llambi / Brenda Lormil / Mary M Mader / Brenton G Mar / Iain Martin / Thomas H McLean / Klaus Michelsen / Yakov Pechersky / Erika Puente-Poushnejad / Kevin Raynor / Dipali Rogala / Ramin Samadani / Alison M Schram / Kelley Shortsleeves / Sweta Swaminathan / Shahein Tajmir / Gege Tan / Yong Tang / Roberto Valverde / Bryan Wehrenberg / Jeremy Wilbur / Bret R Williams / Hongtao Zeng / Hanmo Zhang / W Patrick Walters / Beni B Wolf / David E Shaw / Donald A Bergstrom / James Watters / James S Fraser / Pascal D Fortin / D Randal Kipp / ![]() ![]() Abstract: PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. ...PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor of PI3Kα. RLY-2608 inhibited tumor growth in PIK3CA-mutant xenograft models with minimal impact on insulin, a marker of dysregulated glucose homeostasis. RLY-2608 elicited objective tumor responses in two patients diagnosed with advanced hormone receptor-positive breast cancer with kinase or helical domain PIK3CA mutations, with no observed WT PI3Kα-related toxicities. SIGNIFICANCE: Treatments for PIK3CA-mutant cancers are limited by toxicities associated with the inhibition of WT PI3Kα. Molecular dynamics, cryo-electron microscopy, and DNA-encoded libraries were ...SIGNIFICANCE: Treatments for PIK3CA-mutant cancers are limited by toxicities associated with the inhibition of WT PI3Kα. Molecular dynamics, cryo-electron microscopy, and DNA-encoded libraries were used to develop RLY-2608, a first-in-class inhibitor that demonstrates mutant selectivity in patients. This marks the advance of clinical mutant-selective inhibition that overcomes limitations of orthosteric PI3Kα inhibitors. See related commentary by Gong and Vanhaesebroeck, p. 204 . See related article by Varkaris et al., p. 227 . This article is featured in Selected Articles from This Issue, p. 201. | ||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 915.8 KB | Display | ![]() |
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PDB format | ![]() | 640.5 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 8ts8C ![]() 8ts9C ![]() 8tsaC ![]() 8tsbC ![]() 8tscC ![]() 8tsdC ![]() 8tu6C C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Unit cell |
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Components
#1: Protein | Mass: 123229.391 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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#2: Protein | Mass: 35960.137 Da / Num. of mol.: 1 / Fragment: residues 318-615 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
-Experimental details
-Experiment
Experiment | Method: ![]() |
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Sample preparation
Crystal | Density Matthews: 3.18 Å3/Da / Density % sol: 61.26 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 0.1 M Hepes pH 7.5, 9% PEG-3350 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: ![]() ![]() ![]() |
Detector | Type: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Feb 22, 2019 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.97934 Å / Relative weight: 1 |
Reflection | Resolution: 2.71→74.79 Å / Num. obs: 55887 / % possible obs: 100 % / Redundancy: 7.4 % / Biso Wilson estimate: 99.65 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.076 / Rpim(I) all: 0.03 / Rrim(I) all: 0.081 / Net I/σ(I): 12.8 |
Reflection shell | Resolution: 2.71→2.78 Å / Redundancy: 7.3 % / Num. unique obs: 4066 / CC1/2: 0.321 / % possible all: 99.9 |
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Processing
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Refinement | Method to determine structure: ![]() Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 119.3 Å2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 2.71→74.79 Å
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Refine LS restraints |
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LS refinement shell |
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Refinement TLS params. | Method: refined / Origin x: -11.9252717093 Å / Origin y: -4.17235477794 Å / Origin z: 19.4427456437 Å
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Refinement TLS group | Selection details: all |