+Open data
-Basic information
Entry | Database: PDB / ID: 8ts8 | ||||||
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Title | p85alpha/p110alpha heterodimer H1047R mutant | ||||||
Components |
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Keywords | SIGNALING PROTEIN / Lipid Kinase | ||||||
Function / homology | Function and homology information 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 / phosphatidylinositol 3-kinase regulator activity / response to butyrate / autosome genomic imprinting ...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 / phosphatidylinositol 3-kinase regulator activity / response to butyrate / autosome genomic imprinting / positive regulation of focal adhesion disassembly / IRS-mediated signalling / cellular response to hydrostatic pressure / phosphatidylinositol 3-kinase activator activity / interleukin-18-mediated signaling pathway / PI3K events in ERBB4 signaling / myeloid leukocyte migration / phosphatidylinositol 3-kinase regulatory subunit binding / 1-phosphatidylinositol-3-kinase regulator activity / neurotrophin TRKA receptor binding / Activated NTRK2 signals through PI3K / positive regulation of protein localization to membrane / cis-Golgi network / Activated NTRK3 signals through PI3K / kinase activator activity / ErbB-3 class receptor binding / negative regulation of fibroblast apoptotic process / RHOF GTPase cycle / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IB / vasculature development / transmembrane receptor protein tyrosine kinase adaptor activity / RHOD GTPase cycle / positive regulation of endoplasmic reticulum unfolded protein response / Signaling by cytosolic FGFR1 fusion mutants / regulation of cellular respiration / enzyme-substrate adaptor activity / phosphatidylinositol 3-kinase complex / anoikis / Nephrin family interactions / 1-phosphatidylinositol-4-phosphate 3-kinase activity / RND1 GTPase cycle / Costimulation by the CD28 family / vascular endothelial growth factor signaling pathway / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / RND2 GTPase cycle / MET activates PI3K/AKT signaling / PI3K/AKT activation / RND3 GTPase cycle / positive regulation of leukocyte migration / phosphatidylinositol-4,5-bisphosphate 3-kinase / positive regulation of filopodium assembly / phosphatidylinositol 3-kinase complex, class IA / negative regulation of stress fiber assembly / phosphatidylinositol 3-kinase / relaxation of cardiac muscle / growth hormone receptor signaling pathway / phosphatidylinositol-3-phosphate biosynthetic process / insulin binding / 1-phosphatidylinositol-3-kinase activity / RHOV GTPase cycle / negative regulation of macroautophagy / RHOB GTPase cycle / Signaling by ALK / negative regulation of cell-matrix adhesion / GP1b-IX-V activation signalling / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / protein kinase activator activity / response to dexamethasone / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / RHOJ GTPase cycle / RHOC 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 phosphate biosynthetic process / CDC42 GTPase cycle / RHOU GTPase cycle / PI3K events in ERBB2 signaling / Signaling by ALK fusions and activated point mutants / RHOG GTPase cycle / negative regulation of anoikis / RET signaling / T cell differentiation / regulation of multicellular organism growth / extrinsic apoptotic signaling pathway via death domain receptors / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / intercalated disc / RHOA GTPase cycle / positive regulation of TOR signaling / endothelial cell migration / RAC2 GTPase cycle / RAC3 GTPase cycle / GAB1 signalosome Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.72 Å | ||||||
Authors | Holliday, M. / Tang, Y. / Bulku, A. / Wilbur, J. / Fraser, J. | ||||||
Funding support | 1items
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Citation | Journal: Cancer Discov / Year: 2024 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: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8ts8.cif.gz | 903.7 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8ts8.ent.gz | 625.2 KB | Display | PDB format |
PDBx/mmJSON format | 8ts8.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ts/8ts8 ftp://data.pdbj.org/pub/pdb/validation_reports/ts/8ts8 | HTTPS FTP |
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-Related structure data
Related structure data | 8ts7C 8ts9C 8tsaC 8tsbC 8tscC 8tsdC 8tu6C C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
#1: Protein | Mass: 123248.438 Da / Num. of mol.: 1 / Mutation: H1047R Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CA / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P42336 |
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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.) Homo sapiens (human) / Gene: PIK3R1 / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P27986 |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 3.34 Å3/Da / Density % sol: 63.15 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion, hanging 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: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1.03321 Å |
Detector | Type: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: May 21, 2022 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1.03321 Å / Relative weight: 1 |
Reflection | Resolution: 2.72→95.52 Å / Num. obs: 50359 / % possible obs: 93.6 % / Redundancy: 6.5 % / Biso Wilson estimate: 65.6 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.095 / Rpim(I) all: 0.041 / Rrim(I) all: 0.103 / Net I/σ(I): 12.2 |
Reflection shell | Resolution: 2.72→2.87 Å / Redundancy: 7 % / Num. unique obs: 7722 / CC1/2: 0.805 / % possible all: 100 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.72→95.52 Å / SU ML: 0.3856 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 26.9579 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: 75.37 Å2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 2.72→95.52 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: 11.9074244343 Å / Origin y: -3.93634577638 Å / Origin z: -19.4570718944 Å
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Refinement TLS group | Selection details: all |