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- PDB-5uqw: Crystal structure of human KRAS G12V mutant in complex with GDP -

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Basic information

Entry
Database: PDB / ID: 5uqw
TitleCrystal structure of human KRAS G12V mutant in complex with GDP
ComponentsGTPase KRas
KeywordsHYDROLASE / KRAS / GTPase
Function / homology
Function and homology information


forebrain astrocyte development / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / 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 / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / 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 / protein-membrane adaptor activity / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / homeostasis of number of cells within a tissue / positive regulation of glial cell proliferation / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / FRS-mediated FGFR1 signaling / Tie2 Signaling / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / striated muscle cell differentiation / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / Ras activation upon Ca2+ influx through NMDA receptor / FLT3 Signaling / Signaling by FGFR1 in disease / GRB2 events in ERBB2 signaling / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / SHC1 events in ERBB2 signaling / Downstream signal transduction / Insulin receptor signalling cascade / Constitutive Signaling by Overexpressed ERBB2 / small monomeric GTPase / G protein activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / regulation of long-term neuronal synaptic plasticity / Signaling by ERBB2 TMD/JMD mutants / 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 / cytoplasmic side of plasma membrane / Signaling by SCF-KIT / Regulation of RAS by GAPs / Negative regulation of MAPK pathway / RAS processing / GDP binding / 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 / Signaling by CSF1 (M-CSF) in myeloid cells / MAPK cascade / Signaling by BRAF and RAF1 fusions / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / DAP12 signaling / Ca2+ pathway / gene expression / actin cytoskeleton organization / RAF/MAP kinase cascade / neuron apoptotic process / Ras protein signal transduction / negative regulation of neuron apoptotic process / mitochondrial outer membrane / 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 nucleotide triphosphate hydrolases ...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 nucleotide triphosphate hydrolases / P-loop containing nucleoside triphosphate hydrolase / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsHuang, C.S. / Kaplan, A. / Stockwell, B.R. / Tong, L.
CitationJournal: Cell / Year: 2017
Title: Multivalent Small-Molecule Pan-RAS Inhibitors.
Authors: Welsch, M.E. / Kaplan, A. / Chambers, J.M. / Stokes, M.E. / Bos, P.H. / Zask, A. / Zhang, Y. / Sanchez-Martin, M. / Badgley, M.A. / Huang, C.S. / Tran, T.H. / Akkiraju, H. / Brown, L.M. / ...Authors: Welsch, M.E. / Kaplan, A. / Chambers, J.M. / Stokes, M.E. / Bos, P.H. / Zask, A. / Zhang, Y. / Sanchez-Martin, M. / Badgley, M.A. / Huang, C.S. / Tran, T.H. / Akkiraju, H. / Brown, L.M. / Nandakumar, R. / Cremers, S. / Yang, W.S. / Tong, L. / Olive, K.P. / Ferrando, A. / Stockwell, B.R.
History
DepositionFeb 8, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 22, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2017Group: Author supporting evidence / Category: pdbx_audit_support
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: GTPase KRas
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,9056
Polymers42,9702
Non-polymers9354
Water5,368298
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,9533
Polymers21,4851
Non-polymers4682
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,9533
Polymers21,4851
Non-polymers4682
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)84.344, 84.344, 41.809
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number143
Space group name H-MP3
Components on special symmetry positions
IDModelComponents
11A-1233-

HOH

21A-1241-

HOH

31A-1247-

HOH

41B-1233-

HOH

51B-1234-

HOH

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Components

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


Mass: 21485.207 Da / Num. of mol.: 2 / Fragment: UNP residues 1-169 / Mutation: G12V
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Plasmid: pET15b / Production host: Escherichia coli (E. coli)
References: UniProt: P01116, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE / Guanosine diphosphate


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 298 / Source method: isolated from a natural source / Formula: H2O

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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 Å3/Da / Density % sol: 38.44 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 0.1 M Bis-Tris, 25% w/v PEG3350, pH 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 27, 2012 / Details: MIRRORS
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.075 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.532
11-h,-k,l20.468
ReflectionResolution: 1.5→30 Å / Num. obs: 52602 / % possible obs: 98.6 % / Observed criterion σ(I): -3 / Redundancy: 4.3 % / Rmerge(I) obs: 0.161 / Net I/σ(I): 8.6
Reflection shellResolution: 1.5→1.55 Å / Redundancy: 4 % / Rmerge(I) obs: 0.239 / Mean I/σ(I) obs: 5.7 / % possible all: 90.5

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
REFMAC5.8.0049refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.5→29.69 Å / Cor.coef. Fo:Fc: 0.977 / Cor.coef. Fo:Fc free: 0.963 / SU B: 0.673 / SU ML: 0.027 / Cross valid method: THROUGHOUT / ESU R: 0.01 / ESU R Free: 0.012 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.15272 2654 5 %RANDOM
Rwork0.11666 ---
obs0.11847 49947 99.38 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 16.818 Å2
Baniso -1Baniso -2Baniso -3
1--2.47 Å2-0 Å2-0 Å2
2---2.47 Å2-0 Å2
3---4.95 Å2
Refinement stepCycle: LAST / Resolution: 1.5→29.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2564 0 58 298 2920
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0192671
X-RAY DIFFRACTIONr_bond_other_d00.022519
X-RAY DIFFRACTIONr_angle_refined_deg1.6761.9863622
X-RAY DIFFRACTIONr_angle_other_deg0.74235804
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3275324
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.0324.603126
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.51715477
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.9761517
X-RAY DIFFRACTIONr_chiral_restr0.1040.2414
X-RAY DIFFRACTIONr_gen_planes_refined0.0170.022967
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02590
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.1931.3981293
X-RAY DIFFRACTIONr_mcbond_other2.1611.3961292
X-RAY DIFFRACTIONr_mcangle_it2.9322.0881612
X-RAY DIFFRACTIONr_mcangle_other2.9322.0891613
X-RAY DIFFRACTIONr_scbond_it3.621.7631378
X-RAY DIFFRACTIONr_scbond_other3.6251.7671370
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.8842.5191996
X-RAY DIFFRACTIONr_long_range_B_refined6.04212.6863233
X-RAY DIFFRACTIONr_long_range_B_other5.99212.3653127
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.503→1.542 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.192 197 -
Rwork0.131 3678 -
obs--98.45 %

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