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- PDB-9c15: Crystal structure of the KRAS-p110alpha complex with molecular gl... -

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Basic information

Entry
Database: PDB / ID: 9c15
TitleCrystal structure of the KRAS-p110alpha complex with molecular glue D927
Components
  • GTPase KRas
  • Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
KeywordsONCOPROTEIN / RAS / KRAS / PI3Kalpha / p110alpha / PIK3CA / glue
Function / homology
Function and homology information


response to muscle inactivity / negative regulation of actin filament depolymerization / regulation of actin filament organization / response to L-leucine / 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 / regulation of actin filament organization / response to L-leucine / 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 / Activated NTRK2 signals through PI3K / negative regulation of fibroblast apoptotic process / Activated NTRK3 signals through PI3K / phosphatidylinositol 3-kinase complex, class IB / positive regulation of protein localization to membrane / 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 / relaxation of cardiac muscle / 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 / vascular endothelial growth factor signaling pathway / phosphatidylinositol 3-kinase / GMP binding / response to mineralocorticoid / forebrain astrocyte development / 1-phosphatidylinositol-3-kinase activity / Signaling by ALK / LRR domain binding / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / negative regulation of macroautophagy / negative regulation of epithelial cell differentiation / response to isolation stress / PI-3K cascade:FGFR2 / response to dexamethasone / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR4 / response to gravity / type I pneumocyte differentiation / PI-3K cascade:FGFR1 / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / Rac protein signal transduction / phosphatidylinositol phosphate biosynthetic process / Synthesis of PIPs at the plasma membrane / positive regulation of Rac protein signal transduction / energy homeostasis / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / myoblast proliferation / skeletal muscle cell differentiation / RET signaling / negative regulation of anoikis / RAS signaling downstream of NF1 loss-of-function variants / PI3K events in ERBB2 signaling / insulin receptor substrate binding / RUNX3 regulates p14-ARF / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / intercalated disc / protein kinase activator activity / SOS-mediated signalling / Activated NTRK3 signals through RAS / regulation of multicellular organism growth / Activated NTRK2 signals through RAS / CD28 dependent PI3K/Akt signaling / positive regulation of TOR signaling / SHC1 events in ERBB4 signaling / Role of LAT2/NTAL/LAB on calcium mobilization / RAC2 GTPase cycle / Interleukin receptor SHC signaling / cardiac muscle cell proliferation / Signalling to RAS / Role of phospholipids in phagocytosis / GAB1 signalosome / adipose tissue development / phagocytosis / endothelial cell migration / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Estrogen-stimulated signaling through PRKCZ / glial cell proliferation / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants
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. / Small GTPase, Ras-type / 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 / Small GTPase Ras domain profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / C2 domain superfamily / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Small GTP-binding protein domain / Armadillo-type fold / Ubiquitin-like domain superfamily / Protein kinase-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / ISOPROPYL ALCOHOL / GTPase KRas / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.81 Å
AuthorsYan, W. / Czyzyk, D.J. / Simanshu, D.K.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)75N91019D00024 United States
CitationJournal: Nat Commun / Year: 2025
Title: Structural insights into isoform-specific RAS-PI3K alpha interactions and the role of RAS in PI3K alpha activation.
Authors: Czyzyk, D. / Yan, W. / Messing, S. / Gillette, W. / Tsuji, T. / Yamaguchi, M. / Furuzono, S. / Turner, D.M. / Esposito, D. / Nissley, D.V. / McCormick, F. / Simanshu, D.K.
History
DepositionMay 28, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 22, 2025Provider: repository / Type: Initial release

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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: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)132,5068
Polymers131,3622
Non-polymers1,1436
Water68538
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)58.300, 126.390, 112.940
Angle α, β, γ (deg.)90.000, 105.110, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 2 types, 2 molecules AB

#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: 112033.430 Da / Num. of mol.: 1 / Mutation: W1057A, I1058A, F1059A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3CA / Production host: Trichoplacea (invertebrata)
References: UniProt: P42336, phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
#2: Protein GTPase KRas / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras


Mass: 19328.811 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli (E. coli) / References: UniProt: P01116

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Non-polymers , 5 types, 44 molecules

#3: Chemical ChemComp-A1ATF / 2-[3-fluoro-4-({(7P)-7-[2-(2-methoxyethoxy)phenyl]thieno[2,3-d]pyridazin-4-yl}amino)phenyl]acetamide


Mass: 452.501 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H21FN4O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-IPA / ISOPROPYL ALCOHOL / 2-PROPANOL


Mass: 60.095 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O / Comment: alkaloid*YM
#6: Chemical ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER


Mass: 522.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N6O13P3 / Feature type: SUBJECT OF INVESTIGATION
Comment: GppNHp, GMPPNP, energy-carrying molecule analogue*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 38 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 3.17 Å3/Da / Density % sol: 61.2 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 0.1 M Tris, 0.1 M NaCl, 15% PEG 20K

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 15, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.81→45.54 Å / Num. obs: 37819 / % possible obs: 98.1 % / Redundancy: 3.6 % / CC1/2: 0.996 / Rmerge(I) obs: 0.093 / Rrim(I) all: 0.111 / Net I/σ(I): 10.85
Reflection shellResolution: 2.81→2.99 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.771 / Mean I/σ(I) obs: 1.83 / Num. unique obs: 5718 / CC1/2: 0.749 / Rrim(I) all: 0.925 / % possible all: 92.3

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Processing

Software
NameVersionClassification
PHENIX1.18_3845refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.81→45.54 Å / SU ML: 0.43 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 27.04 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2342 1889 5 %
Rwork0.2028 35884 -
obs0.2044 37773 98.21 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 201.34 Å2 / Biso mean: 81.6717 Å2 / Biso min: 28.37 Å2
Refinement stepCycle: final / Resolution: 2.81→45.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8345 0 74 38 8457
Biso mean--100.52 63.23 -
Num. residues----1055
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 13

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.81-2.890.40061270.37942430255787
2.89-2.970.40311460.31322761290799
2.97-3.070.30881440.26612759290398
3.07-3.180.31071460.253727652911100
3.18-3.310.30511480.249928162964100
3.31-3.460.27281470.24582779292699
3.46-3.640.25771470.20927932940100
3.64-3.870.23171460.18942781292799
3.87-4.160.22321460.18142773291999
4.16-4.580.2071460.16742765291199
4.58-5.250.19881480.162328132961100
5.25-6.60.22241490.2128262975100
6.61-45.540.17611490.17842823297299
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)
10.83360.08140.14982.1831-0.92931.40440.0243-0.0995-0.07290.0505-0.0725-0.20240.03980.00280.06830.3738-0.0365-0.0290.4317-0.00120.565923.144711.726713.0023
22.7417-1.15491.75682.6854-0.5462.32850.1831-0.0828-0.3112-0.58080.02840.50230.0203-0.0619-0.1020.6201-0.02610.03170.40150.14060.767921.430437.5915-9.2815
31.56140.7833-0.25352.4423-0.17030.88320.1188-0.0939-0.1460.2268-0.1437-0.1223-0.0813-0.04950.05960.3369-0.0072-0.00680.35210.03250.370614.553118.933111.9785
42.51920.4376-0.66522.5348-0.29682.84820.2304-0.29420.28450.3328-0.09390.4805-0.1037-0.7274-0.00480.5473-0.0570.06980.6621-0.09750.5962-2.263926.671829.1493
53.3678-0.8029-0.50441.59391.40124.38550.1188-0.3723-0.92240.6107-0.5297-0.23120.59250.09090.450.9706-0.3477-0.24780.8410.25980.98564.8368-20.332941.846
61.0415-0.66410.94141.2076-0.9933.50640.2285-1.0635-0.83450.4436-0.4379-0.61720.5449-0.2520.23621.1809-0.2832-0.27791.0650.55671.121917.0382-18.735247.9983
72.70520.2903-1.15144.6218-1.77932.14770.4152-0.7657-0.27610.6265-0.20320.25950.4719-0.61-0.22171.225-0.2769-0.08111.07340.3780.80026.6791-12.504545.758
80.62160.18-0.95591.6668-1.68232.69590.2625-0.6143-0.36320.496-0.0805-0.2387-0.0055-0.233-0.61061.1333-0.4523-0.24531.27110.63040.91196.5035-17.725555.9584
91.6109-0.8820.82471.4851-0.65280.46210.0324-0.7266-0.28130.7654-0.23120.0656-0.208-0.0065-0.20850.8205-0.31590.14081.77540.3310.6512-0.1456-10.601158.0964
100.64020.10030.80342.3617-0.52491.675-0.2011-0.4367-0.23190.05790.25180.53810.4842-0.208-0.1151.2988-0.6072-0.35481.73760.8041.2772-2.1754-18.373152.1377
111.53430.60920.83652.87-0.70430.95870.60940.49590.1528-0.25220.21120.44960.5851-0.1842-0.4491.8181-0.3965-0.22741.64890.63241.058114.4297-23.602467.0117
120.4208-0.08630.30371.27061.1581.40860.1955-0.1275-0.49810.7721-0.2593-0.31110.5323-1.21160.02941.3206-0.46540.09311.70130.67831.1768-0.7549-23.858165.0444
130.57230.60270.82351.31750.12772.04630.17820.0326-0.34380.7745-0.1778-0.54710.6624-0.66810.04071.4769-0.449-0.12481.5650.81361.70729.1745-26.09857.0345
140.22310.31930.08542.41380.35192.0657-0.17080.0662-1.00620.3937-0.0072-0.44730.1051-0.32640.21511.3975-0.4953-0.42571.15610.56981.72722.886-27.744847.1207
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 105 through 392 )A105 - 392
2X-RAY DIFFRACTION2chain 'A' and (resid 393 through 502 )A393 - 502
3X-RAY DIFFRACTION3chain 'A' and (resid 503 through 853 )A503 - 853
4X-RAY DIFFRACTION4chain 'A' and (resid 854 through 1047 )A854 - 1047
5X-RAY DIFFRACTION5chain 'B' and (resid 1 through 10 )B1 - 10
6X-RAY DIFFRACTION6chain 'B' and (resid 11 through 46 )B11 - 46
7X-RAY DIFFRACTION7chain 'B' and (resid 47 through 74 )B47 - 74
8X-RAY DIFFRACTION8chain 'B' and (resid 75 through 86 )B75 - 86
9X-RAY DIFFRACTION9chain 'B' and (resid 87 through 103 )B87 - 103
10X-RAY DIFFRACTION10chain 'B' and (resid 104 through 116 )B104 - 116
11X-RAY DIFFRACTION11chain 'B' and (resid 117 through 126 )B117 - 126
12X-RAY DIFFRACTION12chain 'B' and (resid 127 through 136 )B127 - 136
13X-RAY DIFFRACTION13chain 'B' and (resid 137 through 151 )B137 - 151
14X-RAY DIFFRACTION14chain 'B' and (resid 152 through 167 )B152 - 167

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