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- PDB-4l9w: Crystal Structure of H-Ras G12C, GMPPNP-bound -

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Basic information

Entry
Database: PDB / ID: 4l9w
TitleCrystal Structure of H-Ras G12C, GMPPNP-bound
ComponentsGTPase HRas
KeywordsSIGNALING PROTEIN / GTPase / activating mutant
Function / homology
Function and homology information


phospholipase C activator activity / GTPase complex / oncogene-induced cell senescence / positive regulation of ruffle assembly / negative regulation of GTPase activity / positive regulation of miRNA metabolic process / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / T-helper 1 type immune response / positive regulation of wound healing / defense response to protozoan ...phospholipase C activator activity / GTPase complex / oncogene-induced cell senescence / positive regulation of ruffle assembly / negative regulation of GTPase activity / positive regulation of miRNA metabolic process / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / T-helper 1 type immune response / positive regulation of wound healing / defense response to protozoan / 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 / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / positive regulation of protein targeting to membrane / Signalling to RAS / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / adipose tissue development / 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 / Schwann cell development / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / 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 / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EPHB-mediated forward signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / myelination / 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 / intrinsic apoptotic signaling pathway / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / positive regulation of GTPase activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / positive regulation of epithelial cell proliferation / small monomeric GTPase / VEGFR2 mediated cell proliferation / regulation of actin cytoskeleton organization / animal organ morphogenesis / FCERI mediated MAPK activation / positive regulation of JNK cascade / Signaling by ERBB2 TMD/JMD mutants / RAF activation / positive regulation of MAP kinase activity / 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 / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / cellular response to gamma radiation / G protein activity / positive regulation of type II interferon production / Regulation of RAS by GAPs / endocytosis / 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 / chemotaxis / cellular senescence / positive regulation of fibroblast proliferation / GDP binding / MAPK cascade / Signaling by BRAF and RAF1 fusions / DAP12 signaling / insulin receptor signaling pathway
Similarity search - Function
Small GTPase, Ras-type / small GTPase Ras family profile. / 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 ...Small GTPase, Ras-type / small GTPase Ras family profile. / 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
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GTPase HRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.952 Å
AuthorsOstrem, J.M. / Peters, U. / Sos, M.L. / Wells, J.A. / Shokat, K.M.
CitationJournal: Nature / Year: 2013
Title: K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions.
Authors: Ostrem, J.M. / Peters, U. / Sos, M.L. / Wells, J.A. / Shokat, K.M.
History
DepositionJun 18, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 27, 2013Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2013Group: Database references
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software
Revision 1.3Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
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.ptnr1_label_seq_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.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _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_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 / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: GTPase HRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,9515
Polymers19,3251
Non-polymers6274
Water2,594144
1
A: GTPase HRas
hetero molecules

A: GTPase HRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,90310
Polymers38,6492
Non-polymers1,2538
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation17_555x-y+1/3,-y+2/3,-z+2/31
Buried area3970 Å2
ΔGint-51 kcal/mol
Surface area13650 Å2
MethodPISA
2
A: GTPase HRas
hetero molecules

A: GTPase HRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,90310
Polymers38,6492
Non-polymers1,2538
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation10_455y-1/3,x+1/3,-z+1/31
Buried area3230 Å2
ΔGint-50 kcal/mol
Surface area14300 Å2
MethodPISA
Unit cell
Length a, b, c (Å)89.148, 89.148, 136.314
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number155
Space group name H-MH32
Components on special symmetry positions
IDModelComponents
11A-204-

CA

21A-342-

HOH

31A-371-

HOH

41A-374-

HOH

51A-381-

HOH

61A-417-

HOH

71A-431-

HOH

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Components

#1: Protein GTPase HRas / H-Ras-1 / Ha-Ras / Transforming protein p21 / c-H-ras / p21ras / GTPase HRas / N-terminally processed


Mass: 19324.738 Da / Num. of mol.: 1 / Fragment: GTPase domain, UNP residues 1-166 / Mutation: G12C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HRAS, HRAS1 / Plasmid: ProEx HTb / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P01112, small monomeric GTPase
#2: Chemical ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER


Mass: 522.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N6O13P3
Comment: GppNHp, GMPPNP, energy-carrying molecule analogue*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 144 / 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: 2.7 Å3/Da / Density % sol: 54.4 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 19% PEG3350, 0.2M CaCl2, pH 7.5, vapor diffusion, hanging drop, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 19, 2010
Diffraction measurementDetails: 1.00 degrees, 3.0 sec, detector distance 225.00 mm / Method: \w scans
RadiationMonochromator: Double crystal, Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionAv R equivalents: 0.06 / Number: 168065
ReflectionResolution: 1.95→20 Å / Num. obs: 15394 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 10.9 % / Rmerge(I) obs: 0.06 / Rsym value: 0.06 / Net I/σ(I): 33.957
Reflection shellResolution: 1.95→1.98 Å / Redundancy: 11 % / Rmerge(I) obs: 0.371 / Mean I/σ(I) obs: 7.154 / Rsym value: 0.371 / % possible all: 100
Cell measurementReflection used: 168065

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation2.5 Å20.01 Å
Translation2.5 Å20.01 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASER2.2.4phasing
PHENIXdev_1402refinement
PDB_EXTRACT3.11data extraction
BOSdata collection
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3GFT

3gft


Resolution: 1.952→20 Å / Occupancy max: 1 / Occupancy min: 0.39 / FOM work R set: 0.8676 / SU ML: 0.19 / σ(F): 1.34 / Phase error: 19.72 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.189 1538 10 %
Rwork0.156 --
obs0.1594 15376 99.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 95.61 Å2 / Biso mean: 36.2788 Å2 / Biso min: 17.42 Å2
Refinement stepCycle: LAST / Resolution: 1.952→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1319 0 35 144 1498
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0081376
X-RAY DIFFRACTIONf_angle_d1.1361869
X-RAY DIFFRACTIONf_chiral_restr0.076209
X-RAY DIFFRACTIONf_plane_restr0.004240
X-RAY DIFFRACTIONf_dihedral_angle_d16.091517
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.952-2.01440.28461370.20241230136799
2.0144-2.08640.26531390.188712521391100
2.0864-2.16980.21391380.180912331371100
2.1698-2.26840.25191360.182312401376100
2.2684-2.38780.21151380.175612411379100
2.3878-2.53720.21531390.161812511390100
2.5372-2.73260.2271400.165812531393100
2.7326-3.00680.18681380.171712571395100
3.0068-3.440.17791430.154212761419100
3.44-4.32680.15961420.135412801422100
4.3268-20.01070.16291480.139613251473100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.96210.5151.43053.10561.71912.8254-0.01310.3679-0.0003-0.19560.0407-0.075-0.08340.0216-0.02750.20090.01770.03220.23060.01850.1699-9.283122.589527.5434
22.4566-0.7958-0.64395.34055.53166.279-0.25920.19740.0888-0.3741-0.00030.1928-0.26780.11160.23290.26240.00490.00330.31510.03440.2727-6.864231.346930.0902
32.17291.20982.91528.11457.78119.6522-0.41181.3483-0.3086-1.11720.34820.22050.31190.5752-0.01840.5996-0.07620.08660.86860.06840.59244.000120.63119.8398
45.07621.6494-0.85314.6417-0.57282.8940.04170.1971-0.1052-0.0637-0.0376-0.62560.0390.5094-0.01820.18150.00360.01650.32720.00180.25644.566617.47232.1865
57.69581.5511.06522.13441.8813.33430.1918-0.2467-0.07060.3952-0.1796-0.08750.2671-0.0804-0.03780.2871-0.05030.00820.19770.01580.1668-4.08513.147640.8488
68.05971.3340.06286.95460.42572.35890.5193-1.0180.95610.3301-0.2578-0.6593-0.34240.3765-0.26370.3147-0.01550.07380.3297-0.10080.3833-2.042729.101839.7126
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 1 through 37 )A0
2X-RAY DIFFRACTION2chain 'A' and (resid 38 through 61 )A0
3X-RAY DIFFRACTION3chain 'A' and (resid 62 through 74 )A0
4X-RAY DIFFRACTION4chain 'A' and (resid 75 through 116 )A0
5X-RAY DIFFRACTION5chain 'A' and (resid 117 through 151 )A0
6X-RAY DIFFRACTION6chain 'A' and (resid 152 through 166 )A0

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