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- PDB-8onv: KRAS-G13D in complex with BI-2493 -

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Basic information

Entry
Database: PDB / ID: 8onv
TitleKRAS-G13D in complex with BI-2493
ComponentsGTPase KRas
KeywordsHYDROLASE / KRAS / GTPase / Inhibitor
Function / homology
Function and homology information


forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Rac protein signal transduction / skeletal muscle cell differentiation / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants ...forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Rac protein signal transduction / skeletal muscle cell differentiation / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / Signalling to RAS / glial cell proliferation / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / positive regulation of glial cell proliferation / Signaling by FLT3 ITD and TKD mutants / homeostasis of number of cells within a tissue / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / p38MAPK events / Tie2 Signaling / Signaling by FGFR2 in disease / striated muscle cell differentiation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / Ras activation upon Ca2+ influx through NMDA receptor / GRB2 events in ERBB2 signaling / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / small monomeric GTPase / G protein activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / regulation of long-term neuronal synaptic plasticity / RAF activation / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII / visual learning / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / cytoplasmic side of plasma membrane / Regulation of RAS by GAPs / Negative regulation of MAPK pathway / RAS processing / Signaling by RAF1 mutants / GDP binding / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / Signaling by CSF1 (M-CSF) in myeloid cells / MAPK cascade / Signaling by BRAF and RAF1 fusions / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Ca2+ pathway / gene expression / actin cytoskeleton organization / RAF/MAP kinase cascade / neuron apoptotic process / mitochondrial outer membrane / negative regulation of neuron apoptotic process / Ras protein signal transduction / positive regulation of protein phosphorylation / Golgi membrane / focal adhesion
Similarity search - Function
Small GTPase, Ras-type / small GTPase Ras family profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / 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 / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / Chem-VU6 / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.01 Å
AuthorsBoettcher, J. / Herdeis, L.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nature / Year: 2023
Title: Pan-KRAS inhibitor disables oncogenic signalling and tumour growth.
Authors: Kim, D. / Herdeis, L. / Rudolph, D. / Zhao, Y. / Bottcher, J. / Vides, A. / Ayala-Santos, C.I. / Pourfarjam, Y. / Cuevas-Navarro, A. / Xue, J.Y. / Mantoulidis, A. / Broker, J. / Wunberg, T. ...Authors: Kim, D. / Herdeis, L. / Rudolph, D. / Zhao, Y. / Bottcher, J. / Vides, A. / Ayala-Santos, C.I. / Pourfarjam, Y. / Cuevas-Navarro, A. / Xue, J.Y. / Mantoulidis, A. / Broker, J. / Wunberg, T. / Schaaf, O. / Popow, J. / Wolkerstorfer, B. / Kropatsch, K.G. / Qu, R. / de Stanchina, E. / Sang, B. / Li, C. / McConnell, D.B. / Kraut, N. / Lito, P.
History
DepositionApr 4, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 7, 2023Provider: repository / Type: Initial release
Revision 1.1Jul 19, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _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: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4246
Polymers19,3711
Non-polymers1,0535
Water5,062281
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1190 Å2
ΔGint-16 kcal/mol
Surface area8480 Å2
Unit cell
Length a, b, c (Å)85.799, 40.845, 55.960
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z

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Components

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Protein , 1 types, 1 molecules A

#1: Protein GTPase KRas / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras


Mass: 19370.781 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, small monomeric GTPase

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Non-polymers , 5 types, 286 molecules

#2: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE / Guanosine diphosphate


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-VU6 / (7~{S})-2'-azanyl-3-[2-[(2~{S})-2-methylpiperazin-1-yl]pyrimidin-4-yl]spiro[5,6-dihydro-4~{H}-1,2-benzoxazole-7,4'-6,7-dihydro-5~{H}-1-benzothiophene]-3'-carbonitrile


Mass: 461.582 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H27N7OS / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 281 / 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: 2.53 Å3/Da / Density % sol: 51.4 %
Crystal growTemperature: 278 K / Method: vapor diffusion, hanging drop
Details: 0.2mM MgCl2, 15-27% PEG 2000, 100mM sodium acetate pH=4.4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 S 16M / Detector: PIXEL / Date: Nov 24, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.01→56 Å / Num. obs: 83260 / % possible obs: 93.1 % / Redundancy: 11.8 % / Biso Wilson estimate: 12.04 Å2 / CC1/2: 1 / Net I/σ(I): 20.3
Reflection shellResolution: 1.011→1.097 Å / Num. unique obs: 4164 / CC1/2: 0.7

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Processing

Software
NameVersionClassification
PHENIX1.20_4459refinement
XDSdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.01→36.88 Å / SU ML: 0.0565 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 15.3296
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1565 4237 5.09 %
Rwork0.1336 79008 -
obs0.1347 83245 80.56 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 20.14 Å2
Refinement stepCycle: LAST / Resolution: 1.01→36.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1349 0 70 281 1700
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00811503
X-RAY DIFFRACTIONf_angle_d1.11422048
X-RAY DIFFRACTIONf_chiral_restr0.0848223
X-RAY DIFFRACTIONf_plane_restr0.0109277
X-RAY DIFFRACTIONf_dihedral_angle_d5.7923261
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.01-1.020.459830.34745X-RAY DIFFRACTION1.4
1.02-1.030.248460.3279154X-RAY DIFFRACTION4.77
1.03-1.050.2220.247268X-RAY DIFFRACTION8.42
1.05-1.060.2776280.2457416X-RAY DIFFRACTION13.2
1.06-1.070.2384340.2225773X-RAY DIFFRACTION23.71
1.07-1.090.2508780.23531401X-RAY DIFFRACTION44.03
1.09-1.10.16651060.20051976X-RAY DIFFRACTION60.37
1.1-1.120.24191300.19222528X-RAY DIFFRACTION78.34
1.12-1.140.1741470.17962885X-RAY DIFFRACTION88.32
1.14-1.160.18641630.16123054X-RAY DIFFRACTION95.35
1.16-1.180.14761620.1443183X-RAY DIFFRACTION97.72
1.18-1.20.17121590.1363240X-RAY DIFFRACTION99.01
1.2-1.220.15071410.13083225X-RAY DIFFRACTION99.15
1.22-1.250.15561860.13023225X-RAY DIFFRACTION99.21
1.25-1.270.13991880.12463201X-RAY DIFFRACTION99.56
1.27-1.30.13841890.1233231X-RAY DIFFRACTION99.36
1.3-1.340.14071820.11953226X-RAY DIFFRACTION99.77
1.34-1.370.15511660.12633241X-RAY DIFFRACTION99.65
1.37-1.410.13931740.11843278X-RAY DIFFRACTION99.77
1.41-1.460.13611630.11313267X-RAY DIFFRACTION99.91
1.46-1.510.13421840.11033265X-RAY DIFFRACTION99.97
1.51-1.570.13441660.10743277X-RAY DIFFRACTION100
1.57-1.640.13151910.11863261X-RAY DIFFRACTION99.97
1.64-1.730.13381600.12433282X-RAY DIFFRACTION100
1.73-1.840.14911950.12853273X-RAY DIFFRACTION99.97
1.84-1.980.13761700.12373310X-RAY DIFFRACTION100
1.98-2.180.1421710.12493308X-RAY DIFFRACTION99.97
2.18-2.490.12551790.1243336X-RAY DIFFRACTION99.91
2.49-3.140.17441990.13893370X-RAY DIFFRACTION99.97
3.14-36.880.18491950.14743509X-RAY DIFFRACTION99.65

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