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- PDB-9e8m: Covalent inhibitor VVD-442 bound to the RAS binding domain (RBD) ... -

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Basic information

Entry
Database: PDB / ID: 9e8m
TitleCovalent inhibitor VVD-442 bound to the RAS binding domain (RBD) of PI3Ka
ComponentsPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsPROTEIN BINDING / PI3-kinase subunit alpha / PI3K-alpha / Serine/threonine protein kinase PIK3CA / RAS binding domain
Function / homology
Function and homology information


response to muscle inactivity / negative regulation of actin filament depolymerization / response to L-leucine / regulation of actin filament organization / response to butyrate / IRS-mediated signalling / autosome genomic imprinting / phosphatidylinositol 3-kinase complex / PI3K events in ERBB4 signaling / cellular response to hydrostatic pressure ...response to muscle inactivity / negative regulation of actin filament depolymerization / response to L-leucine / regulation of actin filament organization / response to butyrate / IRS-mediated signalling / autosome genomic imprinting / phosphatidylinositol 3-kinase complex / PI3K events in ERBB4 signaling / cellular response to hydrostatic pressure / regulation of cellular respiration / positive regulation of protein localization to membrane / Activated NTRK2 signals through PI3K / negative regulation of fibroblast apoptotic process / Activated NTRK3 signals through PI3K / phosphatidylinositol 3-kinase complex, class IB / vasculature development / 1-phosphatidylinositol-4-phosphate 3-kinase activity / Signaling by cytosolic FGFR1 fusion mutants / Co-stimulation by ICOS / cardiac muscle cell contraction / phosphatidylinositol 3-kinase complex, class IA / Nephrin family interactions / anoikis / Signaling by LTK in cancer / phosphatidylinositol-3-phosphate biosynthetic process / Signaling by LTK / MET activates PI3K/AKT signaling / PI3K/AKT activation / 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity / phosphatidylinositol-4,5-bisphosphate 3-kinase / phosphatidylinositol 3-kinase / vascular endothelial growth factor signaling pathway / relaxation of cardiac muscle / 1-phosphatidylinositol-3-kinase activity / Signaling by ALK / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / negative regulation of macroautophagy / PI-3K cascade:FGFR2 / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / phosphatidylinositol phosphate biosynthetic process / Synthesis of PIPs at the plasma membrane / response to dexamethasone / negative regulation of anoikis / RET signaling / PI3K events in ERBB2 signaling / protein kinase activator activity / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / regulation of multicellular organism growth / intercalated disc / CD28 dependent PI3K/Akt signaling / positive regulation of TOR signaling / RAC2 GTPase cycle / Role of LAT2/NTAL/LAB on calcium mobilization / Interleukin receptor SHC signaling / GAB1 signalosome / Role of phospholipids in phagocytosis / adipose tissue development / phagocytosis / endothelial cell migration / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / Signaling by FGFR4 in disease / positive regulation of lamellipodium assembly / energy homeostasis / Signaling by FLT3 ITD and TKD mutants / cardiac muscle contraction / GPVI-mediated activation cascade / Signaling by FGFR3 in disease / Tie2 Signaling / Signaling by FGFR2 in disease / response to muscle stretch / T cell costimulation / RAC1 GTPase cycle / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / Downstream signal transduction / insulin-like growth factor receptor signaling pathway / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / liver development / response to activity / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Regulation of signaling by CBL / positive regulation of smooth muscle cell proliferation / cellular response to glucose stimulus / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / platelet activation / VEGFA-VEGFR2 Pathway / epidermal growth factor receptor signaling pathway / cellular response to insulin stimulus / glucose metabolic process
Similarity search - Function
PI3Kalpha, catalytic domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / 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 ...PI3Kalpha, catalytic domain / PI3-kinase family, p85-binding domain / PI3-kinase family, p85-binding domain / 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 / 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 / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.827 Å
AuthorsBernard, S.M. / Tamiya, J.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Biorxiv / Year: 2024
Title: Covalent inhibitors of the RAS binding domain of PI3K alpha impair tumor growth driven by RAS and HER2.
Authors: Klebba, J.E. / Roy, N. / Bernard, S.M. / Grabow, S. / Hoffman, M.A. / Miao, H. / Tamiya, J. / Wang, J. / Berry, C. / Esparza-Oros, A. / Lin, R. / Liu, Y. / Pariollaud, M. / Parker, H. / ...Authors: Klebba, J.E. / Roy, N. / Bernard, S.M. / Grabow, S. / Hoffman, M.A. / Miao, H. / Tamiya, J. / Wang, J. / Berry, C. / Esparza-Oros, A. / Lin, R. / Liu, Y. / Pariollaud, M. / Parker, H. / Mochalkin, I. / Rana, S. / Snead, A.N. / Walton, E.J. / Wyrick, T.E. / Aitichson, E. / Bedke, K. / Brannon, J.C. / Chick, J.M. / Hee, K. / Horning, B.D. / Ismail, M. / Lamb, K.N. / Lin, W. / Metzger, J. / Pastuszka, M.K. / Pollock, J. / Sigler, J.J. / Tomaschko, M. / Tran, E. / Kinsella, T.M. / Molina-Arcas, M. / Simon, G.M. / Weinstein, D.S. / Downward, J. / Patricelli, M.P.
History
DepositionNov 5, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 1, 2025Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2025Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title

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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 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,8194
Polymers33,6002
Non-polymers1,2202
Water1,22568
1
A: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,4102
Polymers16,8001
Non-polymers6101
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,4102
Polymers16,8001
Non-polymers6101
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)62.390, 88.303, 139.000
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

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


Mass: 16799.793 Da / Num. of mol.: 2 / Fragment: Ras Binding Domain (RBD)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CA / Production host: Escherichia coli (E. coli)
References: UniProt: P42336, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-A1BF9 / 1-[(1P)-5-bromo-2'-chloro[1,1'-biphenyl]-2-sulfonyl]-4-fluoro-N-[(2S)-4-(methanesulfonyl)butan-2-yl]piperidine-4-carboxamide


Mass: 609.956 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H27BrClFN2O5S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 68 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.85 Å3/Da / Density % sol: 56.83 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 5.5 / Details: 4.8 M ammonium acetate, 0.1 M MES pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1.00003 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 28, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00003 Å / Relative weight: 1
ReflectionResolution: 2.827→47.887 Å / Num. obs: 9522 / % possible obs: 99.9 % / Redundancy: 5.1 % / CC1/2: 0.982 / Net I/σ(I): 6.4
Reflection shellResolution: 2.83→2.98 Å / Num. unique obs: 1365 / CC1/2: 0.621

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Processing

Software
NameVersionClassification
REFMAC5.8.0405refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.827→47.887 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.892 / SU B: 34.262 / SU ML: 0.321 / Cross valid method: FREE R-VALUE / ESU R Free: 0.397
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.268 485 5.106 %
Rwork0.1909 9013 -
all0.195 --
obs-9498 99.895 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 40.497 Å2
Baniso -1Baniso -2Baniso -3
1--0.483 Å20 Å2-0 Å2
2---0.321 Å20 Å2
3---0.804 Å2
Refinement stepCycle: LAST / Resolution: 2.827→47.887 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2245 0 70 68 2383
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0122371
X-RAY DIFFRACTIONr_bond_other_d0.0010.0162325
X-RAY DIFFRACTIONr_angle_refined_deg1.7381.7043215
X-RAY DIFFRACTIONr_angle_other_deg0.5371.65390
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.925272
X-RAY DIFFRACTIONr_dihedral_angle_2_deg7.697510
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.19310453
X-RAY DIFFRACTIONr_dihedral_angle_6_deg15.0551092
X-RAY DIFFRACTIONr_chiral_restr0.090.2356
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022574
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02492
X-RAY DIFFRACTIONr_nbd_refined0.2390.2503
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1990.22318
X-RAY DIFFRACTIONr_nbtor_refined0.1930.21101
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0910.21385
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.150.254
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.040.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1340.22
X-RAY DIFFRACTIONr_nbd_other0.1540.280
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1710.29
X-RAY DIFFRACTIONr_mcbond_it2.4552.8321097
X-RAY DIFFRACTIONr_mcbond_other2.4482.8331097
X-RAY DIFFRACTIONr_mcangle_it4.15.0821368
X-RAY DIFFRACTIONr_mcangle_other4.15.081368
X-RAY DIFFRACTIONr_scbond_it3.5763.2961274
X-RAY DIFFRACTIONr_scbond_other3.5753.2971275
X-RAY DIFFRACTIONr_scangle_it5.7685.9261847
X-RAY DIFFRACTIONr_scangle_other5.7665.9261848
X-RAY DIFFRACTIONr_lrange_it8.85428.012637
X-RAY DIFFRACTIONr_lrange_other8.84927.7392636
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.827-2.90.366280.3146340.3166640.910.9399.69880.298
2.9-2.980.305310.3046590.3046900.930.9351000.281
2.98-3.0660.352290.2416090.2466380.9430.9581000.212
3.066-3.160.305430.2326090.2376520.9330.9641000.206
3.16-3.2630.338270.2265740.2316020.940.96699.83390.194
3.263-3.3770.294380.2055740.216120.9440.9721000.182
3.377-3.5030.305350.1825270.1895620.9470.9771000.16
3.503-3.6460.273270.1775390.1815660.970.9811000.153
3.646-3.8070.228310.1725040.1755360.9670.98499.81340.155
3.807-3.9910.24270.1634790.1685070.9710.98599.80280.149
3.991-4.2060.191250.1724690.1734940.9760.9821000.154
4.206-4.4590.222220.1634500.1674720.9760.9841000.149
4.459-4.7630.242260.1414030.1474290.9690.9871000.132
4.763-5.1410.202160.1533940.1554110.9630.98699.75670.139
5.141-5.6250.262200.1783600.1823800.9660.9821000.159
5.625-6.2780.16560.183470.183530.9870.9811000.166
6.278-7.2290.438140.1852910.1933050.9070.9791000.167
7.229-8.8030.168130.1512650.1522790.9830.98599.64160.147
8.803-12.2450.168120.1521990.1532110.9770.9831000.152
12.245-47.8870.521150.3241270.3431430.8670.93699.30070.307
Refinement TLS params.

Method: refined / 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)
11.20630.5804-0.11980.46610.15880.2647-0.04190.09450.08130.00130.06520.020.02860.0298-0.02330.0042-0.0017-0.00820.21610.01940.0516-13.046-22.948-3.723
21.34150.0019-0.52840.0642-0.30321.69390.0995-0.10740.2156-0.03230.05480.01380.1395-0.0978-0.15430.03430.01290.00620.2713-0.01840.0382-17.981-16.55622.723
Refinement TLS groupSelection: ALL

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