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- PDB-8tgd: STX-478, a Mutant-Selective, Allosteric Inhibitor bound to H1047R... -

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Basic information

Entry
Database: PDB / ID: 8tgd
TitleSTX-478, a Mutant-Selective, Allosteric Inhibitor bound to H1047R PI3Kalpha
Components(Phosphatidylinositol ...) x 2
KeywordsTRANSFERASE/TRANSFERSE INHIBITOR / Kinase / Inhibitor / TRANSFERASE / TRANSFERASE-TRANSFERSE INHIBITOR complex
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 / positive regulation of focal adhesion disassembly ...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 / positive regulation of focal adhesion disassembly / autosome genomic imprinting / 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 / 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 / cis-Golgi network / Activated NTRK3 signals through PI3K / ErbB-3 class receptor binding / negative regulation of fibroblast apoptotic process / RHOF GTPase cycle / kinase activator activity / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IB / vasculature development / transmembrane receptor protein tyrosine kinase adaptor activity / RHOD GTPase cycle / Signaling by cytosolic FGFR1 fusion mutants / regulation of cellular respiration / positive regulation of endoplasmic reticulum unfolded protein response / enzyme-substrate adaptor activity / phosphatidylinositol 3-kinase complex, class IA / anoikis / phosphatidylinositol 3-kinase complex / Nephrin family interactions / RND1 GTPase cycle / Costimulation by the CD28 family / relaxation of cardiac muscle / 1-phosphatidylinositol-4-phosphate 3-kinase activity / 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 / positive regulation of filopodium assembly / phosphatidylinositol-4,5-bisphosphate 3-kinase / vascular endothelial growth factor signaling pathway / negative regulation of stress fiber assembly / phosphatidylinositol 3-kinase / growth hormone receptor signaling pathway / insulin binding / phosphatidylinositol-3-phosphate biosynthetic process / RHOV GTPase cycle / negative regulation of macroautophagy / 1-phosphatidylinositol-3-kinase activity / RHOB GTPase cycle / negative regulation of cell-matrix adhesion / Signaling by ALK / 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 / RHOJ GTPase cycle / PI-3K cascade:FGFR4 / RHOC GTPase cycle / PI-3K cascade:FGFR1 / negative regulation of osteoclast differentiation / intracellular glucose homeostasis / phosphatidylinositol-mediated signaling / phosphatidylinositol phosphate biosynthetic process / CD28 dependent PI3K/Akt signaling / Synthesis of PIPs at the plasma membrane / CDC42 GTPase cycle / RHOU GTPase cycle / PI3K events in ERBB2 signaling / negative regulation of anoikis / RHOG GTPase cycle / intercalated disc / T cell differentiation / RET signaling / 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 / RHOA GTPase cycle / positive regulation of TOR signaling / endothelial cell migration / RAC2 GTPase cycle / RAC3 GTPase cycle / Role of phospholipids in phagocytosis
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. / Phosphoinositide 3-kinase C2 / Phosphoinositide 3-kinase, region postulated to contain C2 domain / C2 phosphatidylinositol 3-kinase-type domain / C2 phosphatidylinositol 3-kinase (PI3K)-type domain profile. / Phosphoinositide 3-kinase, accessory (PIK) domain superfamily / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Phosphoinositide 3-kinase family, accessory domain (PIK domain) / Rho GTPase activation protein / 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-X3N / Chem-ZWE / 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 / FOURIER SYNTHESIS / Resolution: 2.928 Å
AuthorsHilbert, B. / Brooijmans, N. / Buckbinder, L. / St.Jean Jr., D.J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Cancer Discov / Year: 2023
Title: STX-478, a Mutant-Selective, Allosteric PI3K alpha Inhibitor Spares Metabolic Dysfunction and Improves Therapeutic Response in PI3K alpha-Mutant Xenografts.
Authors: Buckbinder, L. / St Jean Jr., D.J. / Tieu, T. / Ladd, B. / Hilbert, B. / Wang, W. / Alltucker, J.T. / Manimala, S. / Kryukov, G.V. / Brooijmans, N. / Dowdell, G. / Jonsson, P. / Huff, M. / ...Authors: Buckbinder, L. / St Jean Jr., D.J. / Tieu, T. / Ladd, B. / Hilbert, B. / Wang, W. / Alltucker, J.T. / Manimala, S. / Kryukov, G.V. / Brooijmans, N. / Dowdell, G. / Jonsson, P. / Huff, M. / Guzman-Perez, A. / Jackson, E.L. / Goncalves, M.D. / Stuart, D.D.
History
DepositionJul 12, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 6, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 8, 2023Group: 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_author.identifier_ORCID / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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
C: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
D: Phosphatidylinositol 3-kinase regulatory subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)321,75621
Polymers319,3324
Non-polymers2,42417
Water2,522140
1
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)161,09514
Polymers159,6662
Non-polymers1,42912
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8020 Å2
ΔGint10 kcal/mol
Surface area57150 Å2
MethodPISA
2
C: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
D: Phosphatidylinositol 3-kinase regulatory subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)160,6617
Polymers159,6662
Non-polymers9955
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6330 Å2
ΔGint-12 kcal/mol
Surface area56280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)86.154, 124.502, 165.418
Angle α, β, γ (deg.)90, 92.86, 90
Int Tables number4
Space group name H-MP1211

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Components

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Phosphatidylinositol ... , 2 types, 4 molecules ACBD

#1: Protein Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform / PI3-kinase subunit alpha / PI3K-alpha / PI3Kalpha / PtdIns-3-kinase subunit alpha / ...PI3-kinase subunit alpha / PI3K-alpha / PI3Kalpha / PtdIns-3-kinase subunit alpha / Phosphatidylinositol 4 / 5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha / PtdIns-3-kinase subunit p110-alpha / p110alpha / Phosphoinositide 3-kinase alpha / Phosphoinositide-3-kinase catalytic alpha polypeptide / Serine/threonine protein kinase PIK3CA


Mass: 124464.047 Da / Num. of mol.: 2 / Mutation: H1047R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CA / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P42336, phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Protein Phosphatidylinositol 3-kinase regulatory subunit alpha / PI3-kinase regulatory subunit alpha / PI3K regulatory subunit alpha / PtdIns-3-kinase regulatory ...PI3-kinase regulatory subunit alpha / PI3K regulatory subunit alpha / PtdIns-3-kinase regulatory subunit alpha / Phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha / PI3-kinase subunit p85-alpha / PtdIns-3-kinase regulatory subunit p85-alpha


Mass: 35201.758 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3R1, GRB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P27986

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Non-polymers , 4 types, 157 molecules

#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-X3N / N~2~-{(4S,11aP)-2-[(4S)-4-(difluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl}-L-alaninamide


Mass: 407.371 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H19F2N5O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-ZWE / N-(2-aminopyrimidin-5-yl)-N'-[(1R)-1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]urea


Mass: 401.291 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H12F5N5O2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 140 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.98 Å3/Da / Density % sol: 58.74 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.8 / Details: 0.5 M NaCl, 0.1 M MES-NaOH pH 6.8, 5% w/v PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.965459 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Sep 9, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.965459 Å / Relative weight: 1
ReflectionResolution: 2.928→34.42 Å / Num. obs: 55994 / % possible obs: 94.1 % / Redundancy: 4.78 % / CC1/2: 0.998 / Rmerge(I) obs: 0.0967 / Rpim(I) all: 0.0486 / Rrim(I) all: 0.1087 / Net I/σ(I): 11.52
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
6.985-34.424.410.029732.4755990.9990.01510.033599.5
5.541-6.9854.790.07118.8556000.9950.03610.08100
4.836-5.5414.930.074418.1655980.9950.03690.083499.9
4.391-4.8364.330.084214.9156010.9930.04510.09699.5
4.074-4.3914.650.127211.1955980.9880.06550.143899.9
3.833-4.0744.860.21767.3655990.970.10880.244399.9
3.641-3.8334.910.3285.2356000.9290.16290.3677100
3.481-3.6414.970.55973.256000.8410.2750.625999.9
3.335-3.4815.010.83892.155990.6820.41180.937992.3
2.928-3.3354.960.98671.7256000.5820.48731.103965.3

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
XDS20170601data reduction
STARANISO2.3.77data scaling
BUSTER2.11.8phasing
BUSTER2.11.8refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.928→34.42 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.908 / Cross valid method: THROUGHOUT / SU Rfree Blow DPI: 0.479
RfactorNum. reflection% reflectionSelection details
Rfree0.2516 2840 -RANDOM
Rwork0.2175 ---
obs0.2192 55994 74.5 %-
Displacement parametersBiso mean: 132.68 Å2
Baniso -1Baniso -2Baniso -3
1--9.9998 Å20 Å20.4243 Å2
2--4.7415 Å20 Å2
3---5.2583 Å2
Refine analyzeLuzzati coordinate error obs: 0.44 Å
Refinement stepCycle: LAST / Resolution: 2.928→34.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms20845 0 166 140 21151
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00842332HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.8976498HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d12781SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes6607HARMONIC5
X-RAY DIFFRACTIONt_it21483HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion2704SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact33615SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.38
X-RAY DIFFRACTIONt_other_torsion15.26
LS refinement shellResolution: 2.93→3.13 Å
RfactorNum. reflection% reflection
Rfree0.377 68 -
Rwork0.3077 --
obs0.3118 1120 8.15 %
Refinement TLS params.

Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.40590.15070.29950.95970.14220.4921-0.020.0420.0970.0420.00250.02850.0970.02850.0175-0.3024-0.04110.03630.0182-0.08510.161815.8098-16.200679.6458
20.86140.1236-1.03891.3508-1.7631.4285-0.1417-0.00410.0672-0.0041-0.00710.25780.06720.25780.14880.0662-0.1050.0007-0.02180.056-0.00936.1076-40.499476.0895
30.6375-0.5057-0.4530.86720.3291.66080.1961-0.2474-0.4813-0.2474-0.078-0.2235-0.4813-0.2235-0.11810.24820.1577-0.0777-0.16-0.1105-0.313114.5018-1.8623152.894
42.61640.7081-1.85352.2807-2.64194.1314-0.1568-0.3462-0.5676-0.3462-0.1492-0.4517-0.5676-0.45170.3060.30860.1594-0.0359-0.0609-0.1442-0.13485.75622.9326148.9127
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A2 - 1063
2X-RAY DIFFRACTION1{ A|* }A1501 - 2002
3X-RAY DIFFRACTION2{ B|* }B327 - 586
4X-RAY DIFFRACTION3{ C|* }C2 - 1061
5X-RAY DIFFRACTION3{ C|* }C1501 - 2002
6X-RAY DIFFRACTION4{ D|* }D327 - 586

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