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- PDB-9bl0: KRAS G12D Mutant KRAS 1-169 at 298 K bound to MRTX-1133 -

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Basic information

Entry
Database: PDB / ID: 9bl0
TitleKRAS G12D Mutant KRAS 1-169 at 298 K bound to MRTX-1133
ComponentsIsoform 2B of GTPase KRas
KeywordsHYDROLASE / GTPase
Function / homology
Function and homology information


forebrain astrocyte development / negative regulation of epithelial cell differentiation / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / Rac protein signal transduction / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants ...forebrain astrocyte development / negative regulation of epithelial cell differentiation / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / Rac protein signal transduction / positive regulation of Rac protein signal transduction / skeletal muscle cell differentiation / 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 / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / glial cell proliferation / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / 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 CSF3 (G-CSF) / Signaling by FGFR4 in disease / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / protein-membrane adaptor activity / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / Tie2 Signaling / positive regulation of glial cell proliferation / FRS-mediated FGFR1 signaling / homeostasis of number of cells within a tissue / Signaling by FGFR2 in disease / striated muscle cell differentiation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Downstream signal transduction / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in ERBB2 signaling / Insulin receptor signalling cascade / 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 / RAF activation / regulation of long-term neuronal synaptic plasticity / Signaling by ERBB2 TMD/JMD mutants / Signaling by high-kinase activity BRAF mutants / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / visual learning / Signaling by ERBB2 KD Mutants / cytoplasmic side of plasma membrane / Regulation of RAS by GAPs / RAS processing / Signaling by CSF1 (M-CSF) in myeloid cells / Signaling by RAF1 mutants / Negative regulation of MAPK pathway / 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 / G protein activity / actin cytoskeleton organization / Ca2+ pathway / RAF/MAP kinase cascade / neuron apoptotic process / gene expression / negative regulation of neuron apoptotic process / mitochondrial outer membrane / Ras protein signal transduction / Golgi membrane / focal adhesion / GTPase activity
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
Chem-6IC / GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.66 Å
AuthorsXu, M. / Deck, S.L. / Milano, S.K. / Aplin, C. / Cerione, R.A.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)CA201402 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)P30GM124166 United States
CitationJournal: To Be Published
Title: Room Temperature Structures of Oncogenic KRAS-G12D bound to MRTX-1133
Authors: Xu, M. / Deck, S.L. / Milano, S.K. / Aplin, C. / Cerione, R.A.
History
DepositionApr 29, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 7, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Isoform 2B of GTPase KRas
B: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,7528
Polymers38,6152
Non-polymers2,1366
Water2,558142
1
A: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,3764
Polymers19,3081
Non-polymers1,0683
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Isoform 2B of GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,3764
Polymers19,3081
Non-polymers1,0683
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)75.361, 75.361, 203.864
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3
Symmetry operation#1: x,y,z
#2: -y,x-y,z
#3: -x+y,-x,z
#4: x+1/3,y+2/3,z+2/3
#5: -y+1/3,x-y+2/3,z+2/3
#6: -x+y+1/3,-x+2/3,z+2/3
#7: x+2/3,y+1/3,z+1/3
#8: -y+2/3,x-y+1/3,z+1/3
#9: -x+y+2/3,-x+1/3,z+1/3
Components on special symmetry positions
IDModelComponents
11A-341-

HOH

21A-366-

HOH

31B-341-

HOH

41B-374-

HOH

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Components

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


Mass: 19307.680 Da / Num. of mol.: 2 / Mutation: G12D, C51S, C80L, C118S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P01116, small monomeric GTPase
#2: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / 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.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-6IC / 4-(4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-{[(2R,4R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol / MRTX-1133


Mass: 600.633 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C33H31F3N6O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 142 / Source method: isolated from a natural source / Formula: H2O
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: 2.82 Å3/Da / Density % sol: 56.43 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 24% PEG 8000,100 mM Sodium Citrate, 100 mM Ammonium Acetate pH 5.0

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Data collection

DiffractionMean temperature: 298 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CHESS / Beamline: 7B2 / Wavelength: 0.9686 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 25, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9686 Å / Relative weight: 1
ReflectionResolution: 1.66→50 Å / Num. obs: 49291 / % possible obs: 95.66 % / Redundancy: 4.6 % / Biso Wilson estimate: 23.44 Å2 / CC1/2: 0.986 / Rpim(I) all: 0.049 / Rrim(I) all: 0.111 / Net I/σ(I): 3.7
Reflection shellResolution: 1.66→1.68 Å / Num. unique obs: 4322 / CC1/2: 0.204 / Rpim(I) all: 0.77 / Rrim(I) all: 1.205

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Processing

Software
NameVersionClassification
PHENIX(1.21.1_5286: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.66→40.17 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 20.16 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1947 2017 4.1 %
Rwork0.1788 --
obs0.1794 49223 95.66 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.66→40.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2713 0 146 142 3001
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092925
X-RAY DIFFRACTIONf_angle_d1.4453980
X-RAY DIFFRACTIONf_dihedral_angle_d17.5441119
X-RAY DIFFRACTIONf_chiral_restr0.064436
X-RAY DIFFRACTIONf_plane_restr0.01493
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.66-1.70.38071250.40092936X-RAY DIFFRACTION83
1.7-1.740.35221400.35473151X-RAY DIFFRACTION89
1.74-1.790.25561370.28023255X-RAY DIFFRACTION92
1.79-1.850.26471360.22463250X-RAY DIFFRACTION93
1.85-1.920.24391480.20543366X-RAY DIFFRACTION95
1.92-1.990.2211450.20843370X-RAY DIFFRACTION96
2-2.090.22321450.2013433X-RAY DIFFRACTION97
2.09-2.20.18421520.18553426X-RAY DIFFRACTION98
2.2-2.330.19151450.17093496X-RAY DIFFRACTION99
2.33-2.510.25381480.18973499X-RAY DIFFRACTION99
2.51-2.770.18541480.19063489X-RAY DIFFRACTION99
2.77-3.170.21171500.18273512X-RAY DIFFRACTION100
3.17-3.990.16571510.1563492X-RAY DIFFRACTION100
3.99-40.170.1391470.12823531X-RAY DIFFRACTION100

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