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- PDB-8azy: KRAS-G12D in complex with BI-2865 -

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Basic information

Entry
Database: PDB / ID: 8azy
TitleKRAS-G12D in complex with BI-2865
ComponentsGTPase KRas
KeywordsONCOPROTEIN / Inhibitor / Complex / GTPase
Function / homology
Function and homology information


response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation ...response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Rac protein signal transduction / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / myoblast proliferation / skeletal muscle cell differentiation / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / positive regulation of glial cell proliferation / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / cardiac muscle cell proliferation / Signalling to RAS / 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 / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR4 / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / FRS-mediated FGFR1 signaling / p38MAPK events / Signaling by FGFR3 in disease / protein-membrane adaptor activity / Tie2 Signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / Signaling by FLT3 fusion proteins / SHC1 events in EGFR signaling / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / homeostasis of number of cells within a tissue / Downstream signal transduction / GRB2 events in ERBB2 signaling / Insulin receptor signalling cascade / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in ERBB2 signaling / response to glucocorticoid / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / small monomeric GTPase / FCERI mediated MAPK activation / liver development / female pregnancy / RAF activation / Signaling by ERBB2 TMD/JMD mutants / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / Signaling by high-kinase activity BRAF mutants / regulation of long-term neuronal synaptic plasticity / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / visual learning / Signaling by ERBB2 KD Mutants / cytoplasmic side of plasma membrane / cytokine-mediated signaling pathway / Regulation of RAS by GAPs / Signaling by CSF1 (M-CSF) in myeloid cells / 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 / positive regulation of cellular senescence / DAP12 signaling / MAPK cascade / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
Similarity search - Function
Small GTPase, Ras-type / Small GTPase Ras domain 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 nucleotide triphosphate hydrolases ...Small GTPase, Ras-type / Small GTPase Ras domain 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 nucleotide triphosphate hydrolases / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Alpha Beta
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: 1.09 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 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
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

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Assembly

Deposited unit
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,5538
Polymers19,3711
Non-polymers1,1827
Water3,963220
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1260 Å2
ΔGint-13 kcal/mol
Surface area8410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)87.158, 40.545, 55.943
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: 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

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Non-polymers , 5 types, 227 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.: 4 / 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.: 220 / 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: 51.79 %
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: 1.000004 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 18, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.000004 Å / Relative weight: 1
ReflectionResolution: 1.09→36.762 Å / Num. obs: 57094 / % possible obs: 94.9 % / Redundancy: 12.2 % / Biso Wilson estimate: 12.44 Å2 / Rmerge(I) obs: 0.055 / Rsym value: 0.055 / Net I/σ(I): 17.7
Reflection shellResolution: 1.094→1.206 Å / Redundancy: 10.3 % / Rmerge(I) obs: 1.192 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 2856 / Rsym value: 1.192 / % possible all: 75.8

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Processing

Software
NameVersionClassification
PHENIX1.20_4459refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 8AFB

8afb


Resolution: 1.09→36.76 Å / SU ML: 0.0899 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 24.1122
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.1971 2851 4.99 %RANDOM
Rwork0.164 54238 --
obs0.1657 57089 69.09 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 20.48 Å2
Refinement stepCycle: LAST / Resolution: 1.09→36.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1358 0 78 220 1656
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00961486
X-RAY DIFFRACTIONf_angle_d1.11242011
X-RAY DIFFRACTIONf_chiral_restr0.0836218
X-RAY DIFFRACTIONf_plane_restr0.0094262
X-RAY DIFFRACTIONf_dihedral_angle_d5.8363250
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.09-1.110.248360.337593X-RAY DIFFRACTION2.44
1.11-1.130.5318160.3364313X-RAY DIFFRACTION8.05
1.13-1.150.3152290.2982556X-RAY DIFFRACTION14.53
1.15-1.180.284390.2461733X-RAY DIFFRACTION19
1.18-1.20.2965530.2569935X-RAY DIFFRACTION24.12
1.2-1.230.2232670.23711253X-RAY DIFFRACTION32.28
1.23-1.260.2528830.22261590X-RAY DIFFRACTION41
1.26-1.30.25971180.21442112X-RAY DIFFRACTION54.54
1.3-1.330.23511710.2093149X-RAY DIFFRACTION81.15
1.33-1.380.25021940.19993804X-RAY DIFFRACTION97.42
1.38-1.430.23291960.19043909X-RAY DIFFRACTION100
1.43-1.480.23132150.17593895X-RAY DIFFRACTION100
1.48-1.550.18231810.16263948X-RAY DIFFRACTION100
1.55-1.630.17342100.15913922X-RAY DIFFRACTION99.95
1.63-1.740.18611940.15723934X-RAY DIFFRACTION100
1.74-1.870.18741980.1553955X-RAY DIFFRACTION99.98
1.87-2.060.1862200.14683948X-RAY DIFFRACTION100
2.06-2.360.17622180.14853975X-RAY DIFFRACTION99.98
2.36-2.970.18212170.16214019X-RAY DIFFRACTION99.98
2.97-36.760.20162260.16064195X-RAY DIFFRACTION99.95

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