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- PDB-5vbm: Crystal Structure of Small Molecule Disulfide 2C07 Bound to K-Ras... -

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Basic information

Entry
Database: PDB / ID: 5vbm
TitleCrystal Structure of Small Molecule Disulfide 2C07 Bound to K-Ras Cys Light M72C GDP
ComponentsGTPase KRas
KeywordsHYDROLASE / GTPase / Inhibitor / GDP
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
Chem-92V / GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.49 Å
AuthorsGentile, D.R. / Jenkins, M.L. / Moss, S.M. / Burke, J.E. / Shokat, K.M.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)1R01CA190409-01 United States
SU2C Lung Cancer Dream Team United States
CitationJournal: Cell Chem Biol / Year: 2017
Title: Ras Binder Induces a Modified Switch-II Pocket in GTP and GDP States.
Authors: Gentile, D.R. / Rathinaswamy, M.K. / Jenkins, M.L. / Moss, S.M. / Siempelkamp, B.D. / Renslo, A.R. / Burke, J.E. / Shokat, K.M.
History
DepositionMar 29, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 25, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 1, 2017Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jan 3, 2018Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 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 / struct_conn_type
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.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_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_conn_type.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)20,1064
Polymers19,2791
Non-polymers8273
Water1,892105
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)32.600, 41.180, 111.100
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 19278.643 Da / Num. of mol.: 1 / Mutation: M72C, 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 (E. coli) / Strain (production host): BL21 / References: UniProt: P01116
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#4: Chemical ChemComp-92V / 1-(4-methoxyphenyl)-N-(3-sulfanylpropyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide


Mass: 359.367 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H16F3N3O2S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 105 / 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: 1.93 Å3/Da / Density % sol: 36.4 % / Description: Rectangular plates.
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: 33% PEG4000 .1 M Na Citrate (pH 4.6) .2 M Ammonium Acetate .22 M KCl (10% Additive of 2.2 M KCL)

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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: Aug 29, 2014
RadiationMonochromator: Double-crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.49→55.55 Å / Num. obs: 25082 / % possible obs: 98.7 % / Redundancy: 3.7 % / Biso Wilson estimate: 14.64 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.053 / Rpim(I) all: 0.032 / Rrim(I) all: 0.062 / Net I/σ(I): 15.7
Reflection shellResolution: 1.49→1.51 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.255 / Num. unique obs: 1077 / CC1/2: 0.932 / Rpim(I) all: 0.166 / Rrim(I) all: 0.306 / % possible all: 91.8

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Processing

Software
NameVersionClassification
iMOSFLMdata reduction
PHASERphasing
PHENIX1.11.1_2575refinement
Aimless0.3.8data scaling
PDB_EXTRACT3.22data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4LYJ

4lyj


Resolution: 1.49→55.55 Å / SU ML: 0.16 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 19.2
RfactorNum. reflection% reflection
Rfree0.1962 1299 5.19 %
Rwork0.1722 --
obs0.1735 25016 98.34 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 124.56 Å2 / Biso mean: 24.6958 Å2 / Biso min: 7.2 Å2
Refinement stepCycle: final / Resolution: 1.49→55.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1329 0 78 105 1512
Biso mean--20.09 26.96 -
Num. residues----168
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0071414
X-RAY DIFFRACTIONf_angle_d1.1051914
X-RAY DIFFRACTIONf_chiral_restr0.072211
X-RAY DIFFRACTIONf_plane_restr0.006242
X-RAY DIFFRACTIONf_dihedral_angle_d17.44544
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 9

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.486-1.54550.27461550.21812405256093
1.5455-1.61590.23931500.19322556270698
1.6159-1.70110.24331320.18692618275098
1.7011-1.80760.21151190.1842637275698
1.8076-1.94720.21491410.17312634277599
1.9472-2.14320.18581390.169126512790100
2.1432-2.45330.18991640.160826532817100
2.4533-3.09090.19451420.173827342876100
3.0909-55.58880.17681570.16522829298699
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)
12.34241.76560.51782.1834-0.61121.43510.0358-0.2477-0.14850.2917-0.1880.29820.250.01950.12290.154-0.01960.06640.18050.04660.22-15.5627-13.748122.9503
22.88371.293-1.29086.76760.25422.1816-0.0059-0.1730.11840.01020.012-0.1752-0.07190.0071-0.00110.0567-0.0029-0.01310.137-0.02210.045-9.32384.200517.6675
35.46822.5639-0.94515.1436-4.22363.8233-0.1472-0.5034-0.08670.55320.12080.0787-0.3499-1.1856-0.15640.10930.03570.05290.3886-0.02660.1633-19.94166.06722.2794
45.5059-1.21676.70720.7049-2.05338.989-0.205-0.47331.01480.02520.19850.1483-1.2685-0.15710.12410.28350.0437-0.00280.2954-0.12410.2672-10.914313.837523.4926
57.74846.62393.9676.7793.55352.63930.0831-0.26780.00260.181-0.05780.28010.1059-0.0168-0.02080.06670.02160.0190.1903-0.00420.1589-14.5703-3.297223.3931
65.36416.69322.12228.46082.49680.96660.1828-0.5562-0.07990.2183-0.15290.24090.14670.0094-0.03490.11010.010.02920.2090.01920.1782-15.0573-7.731823.2255
73.6943-3.35411.67463.4413-1.00964.66750.1745-0.21510.67130.01890.2713-0.6177-1.10640.5989-0.04140.1826-0.11420.04250.2902-0.11650.2118-1.62735.112921.7123
89.8656-1.4312-7.66945.16150.43839.70180.2119-1.15780.09660.94011.2046-1.0365-0.40561.1527-0.56080.20770.1185-0.00310.5323-0.12490.44951.4346-1.627525.1344
96.4435-3.88110.21846.7453.86523.665-0.6911-0.66140.58660.43540.1337-0.46570.12310.42610.45410.16510.0559-0.0310.23340.0440.2145-0.6131-7.679821.8809
102.3107-1.67740.12593.2868-1.85383.89830.11730.03280.2553-0.2529-0.0375-0.194-0.22810.2326-0.01660.1117-0.02660.02790.0793-0.02890.1097-3.02384.5478.361
117.32460.0882-1.35358.4662-5.27879.3217-0.08480.3292-0.3987-0.3038-0.0044-0.68830.56820.26830.04620.12850.02940.0280.1771-0.020.21164.5737-8.456611.1879
124.2412-2.8251.7215.8533-2.76632.50760.1149-0.0012-0.0422-0.3891-0.06520.0487-0.0811-0.0333-0.04420.0994-0.01420.00110.0859-0.00820.0531-10.24032.20218.5292
133.0502-4.12651.2435.95-1.5813.00730.13-0.2130.24470.0248-0.03630.4592-1.2825-0.532-0.12220.50760.05740.04280.12710.03980.2232-11.155513.83670.6789
146.7134-1.5031-1.55824.6723-1.67615.36550.21270.44760.0327-0.656-0.25360.06050.40130.17240.01920.1890.0314-0.01920.1255-0.0070.0895-7.9795-0.4118-0.25
154.5896-3.6853-0.17095.55951.47112.956-0.06-0.0189-0.0186-0.0972-0.02960.2763-0.1549-0.16750.08590.06920.0092-0.01620.1139-0.02220.1258-18.40252.269911.8231
167.7847-5.14441.11033.9543-1.93016.95420.04610.0777-0.5971-0.24180.08630.73860.156-0.2709-0.02760.1241-0.01310.01040.0984-0.01740.1912-11.9748-15.093411.4089
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain A and resid 0:4)A0 - 4
2X-RAY DIFFRACTION2(chain A and resid 5:22)A5 - 22
3X-RAY DIFFRACTION3(chain A and resid 23:28)A23 - 28
4X-RAY DIFFRACTION4(chain A and resid 29:34)A29 - 34
5X-RAY DIFFRACTION5(chain A and resid 35:49)A35 - 49
6X-RAY DIFFRACTION6(chain A and resid 50:55)A50 - 55
7X-RAY DIFFRACTION7(chain A and resid 56:64)A56 - 64
8X-RAY DIFFRACTION8(chain A and resid 65:70)A65 - 70
9X-RAY DIFFRACTION9(chain A and resid 71:75)A71 - 75
10X-RAY DIFFRACTION10(chain A and resid 76:97)A76 - 97
11X-RAY DIFFRACTION11(chain A and resid 98:107)A98 - 107
12X-RAY DIFFRACTION12(chain A and resid 108:120)A108 - 120
13X-RAY DIFFRACTION13(chain A and resid 121:126)A121 - 126
14X-RAY DIFFRACTION14(chain A and resid 127:142)A127 - 142
15X-RAY DIFFRACTION15(chain A and resid 143:159)A143 - 159
16X-RAY DIFFRACTION16(chain A and resid 160:169)A160 - 169

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