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- PDB-7t47: KRAS G12D (GppCp) with MRTX-1133 -

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Basic information

Entry
Database: PDB / ID: 7t47
TitleKRAS G12D (GppCp) with MRTX-1133
ComponentsGTPase KRas
KeywordsHYDROLASE/INHIBITOR / Oncoprotein / G12D / GCP / GTPase / KRAS4B / Hydrolase-Inhibitor complex
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 / 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 / regulation of synaptic transmission, GABAergic / type I pneumocyte differentiation / 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 / 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 / Constitutive Signaling by EGFRvIII / regulation of long-term neuronal synaptic plasticity / 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
Chem-6IC / ACETATE ION / PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER / GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.27 Å
AuthorsThomas, N.C. / Gunn, R.J. / Lawson, J.D. / Wang, X. / Matthew, M.A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nature / Year: 2022
Title: A Non-covalent KRASG12D Allele Specific Inhibitor Demonstrates Potent Inhibition of KRAS-dependent Signaling and Regression of KRASG12D-mutant Tumors
Authors: Christensen, J. / Hallin, J. / Bowcut, V. / Calinsan, A. / Briere, D. / Hargis, L. / Engstrom, L. / Laguer, J. / Medwid, J. / Vanderpool, D. / Lifset, E. / Trinh, D. / Hoffman, N. / Wang, X. ...Authors: Christensen, J. / Hallin, J. / Bowcut, V. / Calinsan, A. / Briere, D. / Hargis, L. / Engstrom, L. / Laguer, J. / Medwid, J. / Vanderpool, D. / Lifset, E. / Trinh, D. / Hoffman, N. / Wang, X. / Lawson, J. / Gunn, R. / Smith, C. / Thomas, N. / Martinson, M. / Bergstrom, A. / Sullivan, F. / Bouhana, K. / Winski, S. / He, L. / Julio, F.B. / Pavlicek, A. / Hafing, J. / Rahbaek, L. / Marx, M. / Olson, P.
History
DepositionDec 9, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 16, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / 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)23,3067
Polymers21,5651
Non-polymers1,7406
Water4,179232
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2160 Å2
ΔGint-28 kcal/mol
Surface area7760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)40.311, 50.579, 92.903
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab

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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: 21565.117 Da / Num. of mol.: 1 / Fragment: UNP residues 1-164 / 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 (E. coli) / References: UniProt: P01116, small monomeric GTPase

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Non-polymers , 7 types, 238 molecules

#2: 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.: 1 / Source method: obtained synthetically / Formula: C33H31F3N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GCP / PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER


Mass: 521.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H18N5O13P3 / Comment: GMP-PCP, energy-carrying molecule analogue*YM
#4: 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
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#7: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: Mg
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 232 / 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: 2.2 Å3/Da / Density % sol: 43.99 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: 0.1 M Bis-Tris, pH 5.5, 0.1 M sodium acetate, 8% v/v isopropanol, 22% PEG4000

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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: Oct 16, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.27→46.4515 Å / Num. obs: 48107 / % possible obs: 94.48 % / Redundancy: 6.5 % / Biso Wilson estimate: 11.17 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.04256 / Rpim(I) all: 0.01824 / Net I/σ(I): 26.3
Reflection shellResolution: 1.27→1.315 Å / Rmerge(I) obs: 0.1862 / Num. unique obs: 27847 / CC1/2: 0.984 / Rpim(I) all: 0.07941 / % possible all: 88.63

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
PHENIX1.19.2_4158refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 7RPZ

7rpz


Resolution: 1.27→46.45 Å / SU ML: 0.0953 / Cross valid method: FREE R-VALUE / σ(F): 1.4 / Phase error: 15.7656
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1724 2355 4.89 %
Rwork0.1523 45783 -
obs0.1533 48103 94.35 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 16.81 Å2
Refinement stepCycle: LAST / Resolution: 1.27→46.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1349 0 115 232 1696
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01571506
X-RAY DIFFRACTIONf_angle_d1.62052058
X-RAY DIFFRACTIONf_chiral_restr0.1006226
X-RAY DIFFRACTIONf_plane_restr0.0174248
X-RAY DIFFRACTIONf_dihedral_angle_d14.4871562
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.27-1.30.17811520.16552403X-RAY DIFFRACTION86.14
1.3-1.320.17241160.16182494X-RAY DIFFRACTION89.14
1.32-1.350.18321220.15642500X-RAY DIFFRACTION88.94
1.35-1.390.1911340.16732574X-RAY DIFFRACTION90.78
1.39-1.430.1811280.15752579X-RAY DIFFRACTION91.92
1.43-1.470.19941360.1552546X-RAY DIFFRACTION90.06
1.47-1.510.17711230.14542610X-RAY DIFFRACTION92.27
1.51-1.570.16461480.14122612X-RAY DIFFRACTION93.18
1.57-1.630.17521360.1432721X-RAY DIFFRACTION95.3
1.63-1.710.16861490.14742753X-RAY DIFFRACTION97.19
1.71-1.80.16721430.15042783X-RAY DIFFRACTION97.63
1.8-1.910.1751420.15022803X-RAY DIFFRACTION98.4
1.91-2.060.17111310.15132770X-RAY DIFFRACTION97.12
2.06-2.260.17781540.14992847X-RAY DIFFRACTION98.88
2.26-2.590.18241540.1562854X-RAY DIFFRACTION98.82
2.59-3.260.16791330.16092912X-RAY DIFFRACTION99.09
3.26-46.450.16291540.14773022X-RAY DIFFRACTION98.39
Refinement TLS params.Method: refined / Origin x: -19.1792278522 Å / Origin y: -1.19923014864 Å / Origin z: 12.625478583 Å
111213212223313233
T0.0585459375935 Å2-0.00663986458636 Å20.00843749928123 Å2-0.0610983043066 Å20.0017879897296 Å2--0.0622702307552 Å2
L1.14700619375 °2-0.147352334902 °2-0.0785213797012 °2-1.200347156 °20.172872340487 °2--1.26936980369 °2
S-0.0202806619641 Å °0.0163146111466 Å °0.0405063162626 Å °0.050042597719 Å °0.0209563440076 Å °0.0135495304265 Å °0.0250803204247 Å °0.0246399590973 Å °-0.000766888874882 Å °
Refinement TLS groupSelection details: all

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