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- PDB-4luc: Crystal Structure of small molecule disulfide 6 bound to K-Ras G12C -

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Basic information

Entry
Database: PDB / ID: 4luc
TitleCrystal Structure of small molecule disulfide 6 bound to K-Ras G12C
ComponentsGTPase KRas
KeywordsSIGNALING PROTEIN/INHIBITOR / GTPase / GDP bound / SIGNALING PROTEIN-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 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 / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-20G / GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.29 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
DepositionJul 25, 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

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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)40,56310
Polymers38,7062
Non-polymers1,8578
Water5,927329
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)32.822, 39.083, 62.457
Angle α, β, γ (deg.)77.86, 81.54, 77.55
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 19352.785 Da / Num. of mol.: 2 / Fragment: UNP residues 1-169
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS isoform 2B, KRAS2, RASK2 / Plasmid: pJexpress411 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3) / References: UniProt: P01116
#2: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
#3: Chemical ChemComp-20G / N-{1-[(2,4-dichlorophenoxy)acetyl]piperidin-4-yl}-4-sulfanylbutanamide


Mass: 405.339 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H22Cl2N2O3S / Comment: inhibitor*YM
#4: 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
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 329 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsTHE SEQUENCE IN THE STRUCTRUE REPRESENTS ISOFORM 2B OF GTPASE KRAS. THIS ISOFORM DIFFERS FROM THE ...THE SEQUENCE IN THE STRUCTRUE REPRESENTS ISOFORM 2B OF GTPASE KRAS. THIS ISOFORM DIFFERS FROM THE CANONICAL SEQUENCE AS FOLLOW: 151-153 (RVE TO GVD) AND 165-169 (QYRLK TO KHKEK)

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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: 1.96 Å3/Da / Density % sol: 37.4 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 25% PEG8000, 0.1M CaCl2, 0.1M TRIS, 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: 8.2.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 12, 2011
Diffraction measurementDetails: 1.00 degrees, 3.0 sec, detector distance 150.00 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: 0.065 / Number: 270750
ReflectionResolution: 1.29→20 Å / Num. obs: 70575 / % possible obs: 95.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.8 % / Rmerge(I) obs: 0.065 / Rsym value: 0.065 / Net I/σ(I): 13.09
Reflection shellResolution: 1.29→1.31 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.279 / Mean I/σ(I) obs: 4.411 / Rsym value: 0.279 / % possible all: 91.3
Cell measurementReflection used: 270750

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation2.5 Å19.37 Å
Translation2.5 Å19.37 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASER2.3.0phasing
PHENIXdev_1402refinement
PDB_EXTRACT3.11data extraction
BOSdata collection
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.29→19.37 Å / Occupancy max: 1 / Occupancy min: 0.28 / FOM work R set: 0.8824 / SU ML: 0.1 / σ(F): 1.96 / Phase error: 18.9 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1694 1999 2.83 %
Rwork0.1517 --
obs0.1522 70527 94.97 %
Solvent computationShrinkage radii: 1 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 73.11 Å2 / Biso mean: 21.2272 Å2 / Biso min: 7.8 Å2
Refinement stepCycle: LAST / Resolution: 1.29→19.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2674 0 110 329 3113
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.022878
X-RAY DIFFRACTIONf_angle_d1.9283916
X-RAY DIFFRACTIONf_chiral_restr0.115438
X-RAY DIFFRACTIONf_plane_restr0.012495
X-RAY DIFFRACTIONf_dihedral_angle_d19.411108
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.29-1.3220.231350.21154629476489
1.322-1.35770.20991400.20384792493293
1.3577-1.39760.2551390.18844778491793
1.3976-1.44270.21331410.16834853499494
1.4427-1.49430.17711420.16194857499994
1.4943-1.55410.1741420.15454875501795
1.5541-1.62480.21781430.14954870501395
1.6248-1.71040.16181430.14294924506795
1.7104-1.81750.16471450.15034938508396
1.8175-1.95770.18271450.14954987513297
1.9577-2.15450.16711450.14074998514397
2.1545-2.46570.1531470.14564997514498
2.4657-3.10440.17391470.15745068521598
3.1044-19.37220.14461450.14254962510796
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)
13.02821.14921.09083.1270.70964.1524-0.0603-0.28780.21320.23680.0368-0.057-0.2351-0.01310.03020.06720.023-0.00790.1049-0.01880.07874.8248-5.082318.0159
24.1945-1.37690.31733.0349-0.57131.8824-0.0502-0.0844-0.06260.08310.07720.22030.2183-0.4477-0.0230.1058-0.04270.01480.16980.01310.0648-1.9295-15.912219.7263
37.5681-0.90053.27030.9745-0.20681.4513-0.0663-0.4395-0.07430.23790.1870.105-0.1171-0.602-0.09810.15850.03910.01160.35330.03410.1325.8515-7.26327.1642
47.3363-1.49482.56072.38310.13165.0702-0.1788-0.2330.46840.17840.0912-0.0873-0.18480.02640.12030.10260.01170.00190.11470.01340.0679.954-4.987625.1192
56.27350.03533.48154.4416-0.30114.1359-0.1873-0.07490.26590.23680.1920.1852-0.182-0.2580.00880.11580.04750.01560.17380.01340.1272-4.5251.556211.0473
60.9994-0.44470.07473.5478-0.54972.1423-0.06290.09090.0223-0.2371-0.01490.03870.1301-0.13460.08470.0481-0.01290.00080.0835-0.00460.06644.3136-6.05114.6914
71.7688-0.25460.03220.8011-0.06841.8132-0.11340.0945-0.088-0.3702-0.011-0.18340.06510.03390.08280.1005-0.00980.01340.0864-0.00010.06138.6113-10.99416.8921
82.09952.2148-1.86843.2882-2.4553.9336-0.14070.0497-0.1938-0.2204-0.0383-0.20160.38250.12070.18640.09310.02080.01730.09840.00630.102613.3015-14.07657.0827
96.44013.3612-0.36057.6028-0.60464.8411-0.0823-0.16110.17470.0875-0.0147-0.332-0.27470.2290.07540.0810.0096-0.00980.1033-0.0020.081715.2142-5.504418.5675
104.4849-2.21090.68894.6259-1.18864.0324-0.11260.06830.40050.0613-0.0132-0.2352-0.4535-0.08140.13330.0953-0.0247-0.0120.1350.0190.080423.79349.8512-16.4878
114.42541.09190.94782.6855-0.10264.8908-0.0510.2048-0.0362-0.2294-0.08-0.31340.17540.35950.11330.14680.00950.05290.19930.04770.126530.77623.7138-25.4246
125.3482-3.02942.81351.9482-1.46631.5543-0.0350.25340.43220.0165-0.2919-0.2797-0.15720.34850.19190.1475-0.0343-0.0130.32160.09580.224822.872814.5582-24.0468
132.0157-1.05782.61791.1255-1.49454.0014-0.13960.12190.10720.0517-0.0368-0.0662-0.24040.16930.21030.139-0.0353-0.01120.19830.04550.162427.922911.3772-12.3154
140.79590.40010.20133.03440.60224.1419-0.0908-0.0077-0.01270.08490.014-0.08740.1675-0.03770.07950.04620.00240.01650.09860.0160.080722.65011.179-7.8578
150.399-0.18380.13240.1614-0.06160.0438-0.1208-0.1454-0.36840.3453-0.10760.28270.717-0.22170.21250.5096-0.08390.10780.1695-0.02570.250521.4651-12.9174-20.1974
162.0783-0.0763-2.7780.8806-0.16454.8041-0.25440.2268-0.2325-0.18340.02540.03070.5702-0.3820.19090.163-0.05020.01540.1582-0.00290.102415.394-4.3991-15.5819
176.3549-2.2216-2.41725.31221.07247.4325-0.12520.10960.11590.04090.05470.2625-0.3187-0.44150.06050.09310.0027-0.01380.14910.02740.095713.55799.8914-17.1917
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 1 through 15 )A0
2X-RAY DIFFRACTION2chain 'A' and (resid 16 through 37 )A0
3X-RAY DIFFRACTION3chain 'A' and (resid 38 through 46 )A0
4X-RAY DIFFRACTION4chain 'A' and (resid 47 through 57 )A0
5X-RAY DIFFRACTION5chain 'A' and (resid 58 through 74 )A0
6X-RAY DIFFRACTION6chain 'A' and (resid 75 through 103 )A0
7X-RAY DIFFRACTION7chain 'A' and (resid 104 through 126 )A0
8X-RAY DIFFRACTION8chain 'A' and (resid 127 through 151 )A0
9X-RAY DIFFRACTION9chain 'A' and (resid 152 through 168 )A0
10X-RAY DIFFRACTION10chain 'B' and (resid 1 through 15 )B0
11X-RAY DIFFRACTION11chain 'B' and (resid 16 through 37 )B0
12X-RAY DIFFRACTION12chain 'B' and (resid 38 through 46 )B0
13X-RAY DIFFRACTION13chain 'B' and (resid 47 through 74 )B0
14X-RAY DIFFRACTION14chain 'B' and (resid 75 through 116 )B0
15X-RAY DIFFRACTION15chain 'B' and (resid 117 through 126 )B0
16X-RAY DIFFRACTION16chain 'B' and (resid 127 through 151 )B0
17X-RAY DIFFRACTION17chain 'B' and (resid 152 through 168 )B0

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