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- PDB-8azz: KRAS-G12V in complex with BI-2865 -

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Basic information

Entry
Database: PDB / ID: 8azz
TitleKRAS-G12V in complex with BI-2865
ComponentsGTPase KRas
KeywordsONCOPROTEIN / Inhibitor / Complex / GTPase
Function / homology
Function and homology information


forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / type I pneumocyte differentiation / epithelial tube branching involved in lung morphogenesis / 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 / type I pneumocyte differentiation / epithelial tube branching involved in lung morphogenesis / 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 / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / glial cell proliferation / SHC-mediated cascade:FGFR2 / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / Erythropoietin activates RAS / Signaling by CSF3 (G-CSF) / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR2 signaling / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / positive regulation of glial cell proliferation / Signaling by FGFR2 in disease / FRS-mediated FGFR4 signaling / p38MAPK events / Signaling by FGFR3 in disease / homeostasis of number of cells within a tissue / Tie2 Signaling / FRS-mediated FGFR1 signaling / striated muscle cell differentiation / GRB2 events in EGFR signaling / FLT3 Signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / Signaling by FGFR1 in disease / GRB2 events in ERBB2 signaling / CD209 (DC-SIGN) signaling / Ras activation upon Ca2+ influx through NMDA receptor / NCAM signaling for neurite out-growth / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / small monomeric GTPase / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / RAF activation / regulation of long-term neuronal synaptic plasticity / Constitutive Signaling by EGFRvIII / Signaling by high-kinase activity BRAF mutants / Signaling by ERBB2 ECD mutants / MAP2K and MAPK activation / visual learning / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / G protein activity / cytoplasmic side of plasma membrane / Signaling by CSF1 (M-CSF) in myeloid cells / Regulation of RAS by GAPs / RAS processing / Negative regulation of MAPK pathway / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / GDP binding / Signaling by BRAF and RAF1 fusions / MAPK cascade / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Ca2+ pathway / gene expression / actin cytoskeleton organization / RAF/MAP kinase cascade / neuron apoptotic process / negative regulation of neuron apoptotic process / mitochondrial outer membrane / 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-OFU / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.02 Å
AuthorsBoettcher, J. / Herdeis, L.
Funding support Austria, 1items
OrganizationGrant numberCountry
Other private Austria
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
DepositionSep 6, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 21, 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
Revision 1.2Feb 7, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Revision 1.3Feb 14, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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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)20,4136
Polymers19,3551
Non-polymers1,0585
Water4,756264
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1290 Å2
ΔGint-12 kcal/mol
Surface area8320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)86.476, 40.709, 55.989
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab

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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: 19354.824 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, 269 molecules

#2: Chemical ChemComp-GDP / GUANOSINE-5'-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


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-OFU / (4S)-2-azanyl-4-methyl-4-[3-[4-[(1S)-1-[(2S)-1-methylpyrrolidin-1-ium-2-yl]ethoxy]pyrimidin-2-yl]-1,2,4-oxadiazol-5-yl]-6,7-dihydro-5H-1-benzothiophene-3-carbonitrile


Mass: 466.579 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H28N7O2S / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 264 / 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: 2.55 Å3/Da / Density % sol: 51.69 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 0.2mM Magnesium Chloride, 20% 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: X06SA / Wavelength: 0.999824 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 22, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999824 Å / Relative weight: 1
ReflectionResolution: 1.02→55.989 Å / Num. obs: 74206 / % possible obs: 94.5 % / Redundancy: 12.1 % / Biso Wilson estimate: 12.47 Å2 / Rmerge(I) obs: 0.037 / Rsym value: 0.037 / Net I/σ(I): 24.2
Reflection shellResolution: 1.025→1.128 Å / Redundancy: 6 % / Rmerge(I) obs: 0.711 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 3711 / Rsym value: 0.711 / % possible all: 62.6

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Processing

Software
NameVersionClassification
PHENIXdev_4839refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 8AFB

8afb


Resolution: 1.02→34.22 Å / SU ML: 0.0645 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 18.8186
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.1669 3723 5.02 %RANDOM
Rwork0.145 70479 --
obs0.1461 74202 74.28 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 22.96 Å2
Refinement stepCycle: LAST / Resolution: 1.02→34.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1339 0 70 264 1673
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0081503
X-RAY DIFFRACTIONf_angle_d1.04572049
X-RAY DIFFRACTIONf_chiral_restr0.0772226
X-RAY DIFFRACTIONf_plane_restr0.0085268
X-RAY DIFFRACTIONf_dihedral_angle_d14.3805600
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.02-1.040.541420.344648X-RAY DIFFRACTION1.37
1.04-1.050.276350.3175146X-RAY DIFFRACTION4.16
1.05-1.070.3172130.2607246X-RAY DIFFRACTION7.13
1.07-1.080.2099200.2458378X-RAY DIFFRACTION11.07
1.08-1.10.2714320.2299653X-RAY DIFFRACTION18.5
1.1-1.110.2252680.22031003X-RAY DIFFRACTION29.67
1.11-1.130.2579870.21131435X-RAY DIFFRACTION40.98
1.13-1.150.185870.19241757X-RAY DIFFRACTION50.62
1.15-1.170.16041220.17822217X-RAY DIFFRACTION64.19
1.17-1.20.19551520.17912820X-RAY DIFFRACTION81.03
1.2-1.220.19571910.17223288X-RAY DIFFRACTION94.92
1.22-1.250.19921910.16963427X-RAY DIFFRACTION98.5
1.25-1.280.18291620.16353499X-RAY DIFFRACTION98.84
1.28-1.310.16911780.15613469X-RAY DIFFRACTION99.81
1.31-1.340.18321690.15153450X-RAY DIFFRACTION99.34
1.34-1.380.17251780.13973506X-RAY DIFFRACTION99.35
1.38-1.430.18342000.13543470X-RAY DIFFRACTION99.62
1.43-1.480.1611810.13523507X-RAY DIFFRACTION99.7
1.48-1.540.1541680.12573519X-RAY DIFFRACTION99.84
1.54-1.610.15482130.12833496X-RAY DIFFRACTION99.92
1.61-1.690.15131770.13563539X-RAY DIFFRACTION99.95
1.69-1.80.15421840.14223523X-RAY DIFFRACTION100
1.8-1.940.1551930.13893550X-RAY DIFFRACTION99.97
1.94-2.130.16652020.13733530X-RAY DIFFRACTION99.95
2.13-2.440.15281570.13583614X-RAY DIFFRACTION100
2.44-3.070.1581940.14413620X-RAY DIFFRACTION100
3.07-34.220.17551970.14893769X-RAY DIFFRACTION99.52

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