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- PDB-5us4: Crystal structure of human KRAS G12D mutant in complex with GDP -

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Basic information

Entry
Database: PDB / ID: 5us4
TitleCrystal structure of human KRAS G12D mutant in complex with GDP
ComponentsGTPase KRas
KeywordsHYDROLASE / KRAS / GTPase
Function / homology
Function and homology information


forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / 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 / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / 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 / SHC-related events triggered by IGF1R / glial cell proliferation / Activated NTRK2 signals through FRS2 and FRS3 / 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 / SHC-mediated cascade:FGFR2 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / positive regulation of glial cell proliferation / homeostasis of number of cells within a tissue / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / Tie2 Signaling / FRS-mediated FGFR1 signaling / Signaling by FGFR2 in disease / striated muscle cell differentiation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / Ras activation upon Ca2+ influx through NMDA receptor / 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 / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / small monomeric GTPase / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / G protein activity / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / RAF activation / regulation of long-term neuronal synaptic plasticity / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII / MAP2K and MAPK activation / visual learning / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / cytoplasmic side of plasma membrane / Regulation of RAS by GAPs / Negative regulation of MAPK pathway / RAS processing / 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 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 / mitochondrial outer membrane / negative regulation of neuron apoptotic process / 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 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 / MOLECULAR REPLACEMENT / Resolution: 1.83 Å
AuthorsTran, T. / 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 13, 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 7, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.source
Revision 1.3Mar 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_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_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)44,1228
Polymers43,0022
Non-polymers1,1196
Water4,306239
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,0614
Polymers21,5011
Non-polymers5603
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,0614
Polymers21,5011
Non-polymers5603
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)93.822, 93.822, 121.352
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3

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Components

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


Mass: 21501.164 Da / Num. of mol.: 2 / Mutation: G12D
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
#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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 239 / 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: 2.39 Å3/Da / Density % sol: 48.54 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 9.1
Details: 0.2 M sodium phosphate dibasic, 20% w/v PEG3350, pH 9.1

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-003 / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Oct 7, 2015 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.83→50 Å / Num. obs: 33643 / % possible obs: 95.7 % / Observed criterion σ(I): -3 / Redundancy: 2.8 % / Rmerge(I) obs: 0.048 / Net I/σ(I): 19.2
Reflection shellResolution: 1.83→1.9 Å / Redundancy: 2.4 % / Rmerge(I) obs: 0.239 / Mean I/σ(I) obs: 3.7 / % possible all: 97.2

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
PHENIX1.9_1685refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.83→38.525 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 1.97 / Phase error: 19.59
RfactorNum. reflection% reflection
Rfree0.2005 1687 5.02 %
Rwork0.164 --
obs0.1659 33635 95.61 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.83→38.525 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2611 0 70 241 2922
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.022719
X-RAY DIFFRACTIONf_angle_d1.7913673
X-RAY DIFFRACTIONf_dihedral_angle_d16.7141031
X-RAY DIFFRACTIONf_chiral_restr0.262418
X-RAY DIFFRACTIONf_plane_restr0.008464
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8292-1.8830.2611410.21152682X-RAY DIFFRACTION96
1.883-1.94380.23641440.18462745X-RAY DIFFRACTION99
1.9438-2.01330.2621630.17322730X-RAY DIFFRACTION99
2.0133-2.09390.21661340.16852712X-RAY DIFFRACTION98
2.0939-2.18920.1941510.16212765X-RAY DIFFRACTION98
2.1892-2.30460.19621470.15392674X-RAY DIFFRACTION97
2.3046-2.44890.19141280.1662677X-RAY DIFFRACTION97
2.4489-2.6380.21721360.17312690X-RAY DIFFRACTION96
2.638-2.90340.20591290.18142666X-RAY DIFFRACTION95
2.9034-3.32330.18251450.16462611X-RAY DIFFRACTION94
3.3233-4.18620.19431340.14382547X-RAY DIFFRACTION92
4.1862-38.53310.17421350.15442449X-RAY DIFFRACTION88
Refinement TLS params.Method: refined / Origin x: -22.0053 Å / Origin y: 38.1037 Å / Origin z: -11.9575 Å
111213212223313233
T0.1092 Å20.0028 Å2-0.0162 Å2-0.1023 Å2-0.0106 Å2--0.1149 Å2
L1.1286 °20.3251 °2-0.3917 °2-0.7222 °2-0.2345 °2--0.6493 °2
S0.0043 Å °-0.0101 Å °-0.0178 Å °0.0028 Å °0.0056 Å °-0.0102 Å °0.0037 Å °0.0045 Å °-0.0145 Å °
Refinement TLS groupSelection details: all

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