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- PDB-6ark: Crystal Structure of compound 10 covalently bound to K-Ras G12C -

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Basic information

Entry
Database: PDB / ID: 6ark
TitleCrystal Structure of compound 10 covalently bound to K-Ras G12C
ComponentsGTPase KRas
Keywordssignaling protein/inhibitor / DOCKovalent / covalent docking / K-Ras G12C / covalent inhibitors / covalent fragments / SIGNALING PROTEIN / signaling protein-inhibitor complex
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 / 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 / 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) / positive regulation of glial cell proliferation / Signaling by FLT3 ITD and TKD mutants / homeostasis of number of cells within a tissue / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / FRS-mediated FGFR1 signaling / p38MAPK events / Tie2 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 / Signaling by FGFR1 in disease / Ras activation upon Ca2+ influx through NMDA receptor / 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 / G protein activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / regulation of long-term neuronal synaptic plasticity / 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 / 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 / GDP binding / 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 / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / 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
Chem-BQD / GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.75 Å
AuthorsNnadi, C.I. / Jenkins, M.L. / Gentile, D.R. / Bateman, L.A. / Zaidman, D. / Balius, T.E. / Nomura, D.K. / Burke, J.E. / Shokat, K.M. / London, N.
Funding support United States, Israel, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)5R01CA190408-03 United States
Israel Science Foundation1097/16 Israel
National Institutes of Health/National Cancer Institute (NIH/NCI)1F30CA214015-01 United States
CitationJournal: J Chem Inf Model / Year: 2018
Title: Novel K-Ras G12C Switch-II Covalent Binders Destabilize Ras and Accelerate Nucleotide Exchange.
Authors: Nnadi, C.I. / Jenkins, M.L. / Gentile, D.R. / Bateman, L.A. / Zaidman, D. / Balius, T.E. / Nomura, D.K. / Burke, J.E. / Shokat, K.M. / London, N.
History
DepositionAug 22, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 31, 2018Provider: repository / Type: Initial release
Revision 1.1Mar 7, 2018Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 4, 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
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.ptnr2_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,3966
Polymers19,3531
Non-polymers1,0435
Water1,00956
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)94.280, 94.280, 119.550
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number155
Space group name H-MH32

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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: 19352.785 Da / Num. of mol.: 1 / Mutation: G12C, 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 K-12 (bacteria) / References: UniProt: P01116

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Non-polymers , 5 types, 61 molecules

#2: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE / Guanosine diphosphate


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / 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.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-BQD / (3R)-N-(6-bromonaphthalen-2-yl)-3-hydroxy-1-propanoyl-L-prolinamide


Mass: 391.259 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H19BrN2O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


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


Mass: 18.015 Da / Num. of mol.: 56 / 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: 2.64 Å3/Da / Density % sol: 53.44 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 5% PEG 400, 2M (NH4)2SO4, 0.1M HEPES

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 0.999 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Mar 25, 2015
RadiationMonochromator: Double crystal, Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999 Å / Relative weight: 1
ReflectionResolution: 1.75→30.43 Å / Num. obs: 39968 / % possible obs: 100 % / Redundancy: 5.9 % / CC1/2: 0.999 / Rmerge(I) obs: 0.072 / Rpim(I) all: 0.033 / Rrim(I) all: 0.079 / Net I/σ(I): 13.6
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Rpim(I) allRrim(I) all% possible all
1.75-1.785.90.9960.7020.4511.095100
9.09-30.4350.01810.0090.0297.4

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation5.96 Å30.43 Å
Translation5.96 Å30.43 Å

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Processing

Software
NameVersionClassification
PHENIX1.9refinement
Aimless0.3.8data scaling
PDB_EXTRACT3.22data extraction
MOSFLM7.1.3data reduction
PHASER2.5.6phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4L9S

4l9s


Resolution: 1.75→29.881 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 24.57
RfactorNum. reflection% reflection
Rfree0.2314 2116 5.29 %
Rwork0.1937 --
obs0.1957 39968 99.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 405.57 Å2 / Biso mean: 56.871 Å2 / Biso min: 0 Å2
Refinement stepCycle: final / Resolution: 1.75→29.881 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1304 0 110 56 1470
Biso mean--60.74 42.5 -
Num. residues----166
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)
10.09510.03070.11530.885-0.30770.66170.1333-1.1221.76940.23720.0584-0.4337-0.2631-0.00590.06850.29860.01850.06520.3692-0.23170.7325-16.374119.5348-24.6202
22.13920.83460.81910.59340.10650.49550.2403-0.63560.01640.32240.082-0.36460.26070.0060.21180.46390.1129-0.29311.0896-0.69360.9541-8.881318.258-16.046
36.7704-1.5152.67181.7413-2.53363.7142-0.01190.02620.78690.47850.0661-0.2953-0.72950.43680.42040.439-0.0133-0.01890.4064-0.36050.583-22.134224.3819-20.914
43.67170.9121-1.79226.08714.46584.99410.6853-0.3640.89220.69450.5718-0.0066-1.8836-0.262-0.31930.53380.04350.14590.2725-0.04370.3445-28.98826.2251-33.2769
55.28044.9211-2.41458.60853.12118.30220.4949-0.90280.1651-0.25770.00920.16380.03910.4556-0.47570.2184-0.04010.03040.3455-0.19630.4581-20.956217.7697-21.084
64.2082-4.3692-1.55615.1812.84532.90570.5618-0.65110.091.3537-0.3902-0.54580.64140.43790.240.9293-0.02180.08020.7940.07070.5055-25.11178.7698-16.4058
73.8576-4.1787-2.71546.71171.3742.92970.03710.1095-0.65290.0998-0.1307-0.22130.0697-0.01840.08860.2238-0.0097-0.02020.20950.00540.2773-11.52726.9502-28.572
84.73874.7783-4.83844.8411-4.88644.9573-0.49630.098-0.16550.07440.46340.18860.3042-0.37220.08030.28570.01770.00130.3010.03540.3605-18.6910.3737-25.4756
98.95754.3219-4.6973.4088-0.0178.0177-0.4575-0.2094-0.00860.40650.15221.27250.5619-0.50170.13750.3008-0.03770.09560.3021-0.02120.4071-28.48452.2563-27.4368
105.58942.05442.52744.69240.38411.1889-0.21630.7352-0.2739-0.36440.3561-0.5043-0.02760.2793-0.12150.19360.00840.04680.2621-0.06410.3023-8.21758.4466-36.5726
114.1847-0.57271.21520.53820.32631.8584-0.12450.46390.7698-0.05950.2205-0.38770.010.2949-0.14870.17260.0273-0.02330.23440.02140.4064-13.521112.4111-35.7396
122.1932-0.90771.29684.3272-0.64424.17250.12790.02410.6908-0.0014-0.2080.0555-0.0728-0.30120.0320.190.02960.03890.2245-0.0120.3216-25.150816.6037-33.7033
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain A and resid 1:28)A1 - 28
2X-RAY DIFFRACTION2(chain A and resid 29:38)A29 - 38
3X-RAY DIFFRACTION3(chain A and resid 39:43)A39 - 43
4X-RAY DIFFRACTION4(chain A and resid 44:50)A44 - 50
5X-RAY DIFFRACTION5(chain A and resid 51:60)A51 - 60
6X-RAY DIFFRACTION6(chain A and resid 68:74)A68 - 74
7X-RAY DIFFRACTION7(chain A and resid 75:92)A75 - 92
8X-RAY DIFFRACTION8(chain A and resid 93:102)A93 - 102
9X-RAY DIFFRACTION9(chain A and resid 103:110)A103 - 110
10X-RAY DIFFRACTION10(chain A and resid 111:134)A111 - 134
11X-RAY DIFFRACTION11(chain A and resid 135:149)A135 - 149
12X-RAY DIFFRACTION12(chain A and resid 150:169)A150 - 169

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