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- PDB-8tsc: Human PI3K p85alpha/p110alpha H1047R bound to compound 3 -

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Basic information

Entry
Database: PDB / ID: 8tsc
TitleHuman PI3K p85alpha/p110alpha H1047R bound to compound 3
Components
  • Phosphatidylinositol 3-kinase regulatory subunit alpha
  • Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsSIGNALING PROTEIN/INHIBITOR / Lipid kinase / SIGNALING PROTEIN / SIGNALING PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


perinuclear endoplasmic reticulum membrane / response to muscle inactivity / regulation of toll-like receptor 4 signaling pathway / negative regulation of actin filament depolymerization / phosphatidylinositol kinase activity / response to L-leucine / regulation of actin filament organization / response to butyrate / phosphatidylinositol 3-kinase regulator activity / IRS-mediated signalling ...perinuclear endoplasmic reticulum membrane / response to muscle inactivity / regulation of toll-like receptor 4 signaling pathway / negative regulation of actin filament depolymerization / phosphatidylinositol kinase activity / response to L-leucine / regulation of actin filament organization / response to butyrate / phosphatidylinositol 3-kinase regulator activity / IRS-mediated signalling / positive regulation of focal adhesion disassembly / cellular response to hydrostatic pressure / phosphatidylinositol 3-kinase activator activity / autosome genomic imprinting / 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 / negative regulation of fibroblast apoptotic process / cis-Golgi network / ErbB-3 class receptor binding / kinase activator activity / phosphatidylinositol 3-kinase complex, class IB / vasculature development / transmembrane receptor protein tyrosine kinase adaptor activity / RHOF GTPase cycle / regulation of cellular respiration / Signaling by cytosolic FGFR1 fusion mutants / positive regulation of endoplasmic reticulum unfolded protein response / RHOD GTPase cycle / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol 3-kinase complex / enzyme-substrate adaptor activity / Nephrin family interactions / anoikis / Signaling by LTK in cancer / Costimulation by the CD28 family / RND1 GTPase cycle / Signaling by LTK / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / relaxation of cardiac muscle / MET activates PI3K/AKT signaling / positive regulation of leukocyte migration / PI3K/AKT activation / RND2 GTPase cycle / phosphatidylinositol-4,5-bisphosphate 3-kinase / positive regulation of filopodium assembly / RND3 GTPase cycle / growth hormone receptor signaling pathway / vascular endothelial growth factor signaling pathway / negative regulation of stress fiber assembly / phosphatidylinositol 3-kinase / insulin binding / phosphatidylinositol-3-phosphate biosynthetic process / natural killer cell mediated cytotoxicity / 1-phosphatidylinositol-3-kinase activity / RHOV GTPase cycle / negative regulation of cell-matrix adhesion / Signaling by ALK / negative regulation of macroautophagy / 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 / PI-3K cascade:FGFR4 / response to dexamethasone / PI-3K cascade:FGFR1 / RHOC GTPase cycle / RHOJ GTPase cycle / intracellular glucose homeostasis / negative regulation of osteoclast differentiation / Synthesis of PIPs at the plasma membrane / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / CD28 dependent PI3K/Akt signaling / RHOU GTPase cycle / CDC42 GTPase cycle / PI3K events in ERBB2 signaling / negative regulation of anoikis / RET signaling / intercalated disc / Interleukin-3, Interleukin-5 and GM-CSF signaling / insulin receptor substrate binding / T cell differentiation / RHOG GTPase cycle / PI3K Cascade / regulation of multicellular organism growth / extrinsic apoptotic signaling pathway via death domain receptors / endothelial cell migration / positive regulation of TOR signaling / RHOA GTPase cycle
Similarity search - Function
PI3Kalpha, catalytic domain / Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3K p85 subunit, C-terminal SH2 domain / PI3K regulatory subunit p85-related , inter-SH2 domain / PI3K p85 subunit, N-terminal SH2 domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Rho GTPase-activating protein domain ...PI3Kalpha, catalytic domain / Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3K p85 subunit, C-terminal SH2 domain / PI3K regulatory subunit p85-related , inter-SH2 domain / PI3K p85 subunit, N-terminal SH2 domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / Rho GTPase-activating protein domain / RhoGAP domain / Rho GTPase-activating proteins domain profile. / GTPase-activator protein for Rho-like GTPases / Phosphatidylinositol 3-kinase, adaptor-binding domain / Phosphatidylinositol 3-kinase adaptor-binding (PI3K ABD) domain profile. / PI3-kinase family, Ras-binding domain / Phosphatidylinositol 3-kinase Ras-binding (PI3K RBD) domain / PI3-kinase family, ras-binding domain / Phosphatidylinositol 3-kinase Ras-binding (PI3K RBD) domain profile. / C2 phosphatidylinositol 3-kinase-type domain / Phosphoinositide 3-kinase C2 / C2 phosphatidylinositol 3-kinase (PI3K)-type domain profile. / Phosphoinositide 3-kinase, region postulated to contain C2 domain / Rho GTPase activation protein / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase, accessory (PIK) domain superfamily / Phosphoinositide 3-kinase, accessory (PIK) domain / Phosphatidylinositol kinase / PIK helical domain profile. / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / C2 domain superfamily / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-UJC / Phosphatidylinositol 3-kinase regulatory subunit alpha / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.62 Å
AuthorsHolliday, M. / Tang, Y. / Bulku, A. / Wilbur, J. / Fraser, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: 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
DepositionAug 11, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 22, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 21, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
B: Phosphatidylinositol 3-kinase regulatory subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)159,3063
Polymers158,8202
Non-polymers4851
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5990 Å2
ΔGint-23 kcal/mol
Surface area57920 Å2
MethodPISA
Unit cell
Length a, b, c (Å)85.561, 120.281, 190.445
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform


Mass: 122860.016 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
#2: Protein Phosphatidylinositol 3-kinase regulatory subunit alpha


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
#3: Chemical ChemComp-UJC / (1S)-7-[3-fluoro-5-(trifluoromethyl)benzamido]-N-methyl-1-(2-methylphenyl)-3-oxo-2,3-dihydro-1H-isoindole-5-carboxamide


Mass: 485.430 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H19F4N3O3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.26 Å3/Da / Density % sol: 62.31 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 0.1 M Hepes pH 7.5, 9% PEG-3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1.03321 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: May 16, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03321 Å / Relative weight: 1
ReflectionResolution: 3.62→69.72 Å / Num. obs: 23105 / % possible obs: 99.9 % / Redundancy: 6.4 % / Biso Wilson estimate: 131.93 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.108 / Rpim(I) all: 0.046 / Rrim(I) all: 0.118 / Net I/σ(I): 10.5
Reflection shellResolution: 3.62→3.82 Å / Redundancy: 7 % / Num. unique obs: 3317 / CC1/2: 0.776 / % possible all: 100

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Processing

Software
NameVersionClassification
ISOLDEmodel building
PHENIX1.20.1_4487refinement
autoPROCdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.62→69.72 Å / SU ML: 0.4279 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 28.1872
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2545 1122 4.87 %
Rwork0.2161 21914 -
obs0.218 23036 99.73 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 145.11 Å2
Refinement stepCycle: LAST / Resolution: 3.62→69.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10526 0 35 0 10561
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002510784
X-RAY DIFFRACTIONf_angle_d0.572314545
X-RAY DIFFRACTIONf_chiral_restr0.03971569
X-RAY DIFFRACTIONf_plane_restr0.00481863
X-RAY DIFFRACTIONf_dihedral_angle_d13.95074145
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.62-3.780.35421300.29992709X-RAY DIFFRACTION99.96
3.78-3.980.30571480.27872674X-RAY DIFFRACTION99.61
3.98-4.230.31851270.23682712X-RAY DIFFRACTION99.93
4.23-4.560.24681520.20262702X-RAY DIFFRACTION99.83
4.56-5.020.25881470.20762725X-RAY DIFFRACTION99.97
5.02-5.750.26781410.21252732X-RAY DIFFRACTION99.86
5.75-7.240.26861500.23932746X-RAY DIFFRACTION99.55
7.24-69.720.20871270.1892914X-RAY DIFFRACTION99.15
Refinement TLS params.Method: refined / Origin x: 10.8310772854 Å / Origin y: -4.9259008888 Å / Origin z: -19.2608271382 Å
111213212223313233
T0.817412271069 Å2-0.0131336208143 Å20.00899496532305 Å2-0.826419171616 Å20.0499983052009 Å2--0.796635681076 Å2
L0.272634736306 °2-0.0141656563993 °20.0792260266015 °2-0.550443350848 °2-0.140244340897 °2--0.364721705147 °2
S-0.0314573839161 Å °0.104417757991 Å °-0.0453347163666 Å °0.100969846955 Å °-0.0229306161433 Å °0.0882542934165 Å °-0.0969347374514 Å °0.159808854508 Å °2.84635935955E-6 Å °
Refinement TLS groupSelection details: all

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