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- PDB-4m1o: Crystal Structure of small molecule vinylsulfonamide 7 covalently... -

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Basic information

Entry
Database: PDB / ID: 4m1o
TitleCrystal Structure of small molecule vinylsulfonamide 7 covalently bound to K-Ras G12C
ComponentsK-Ras GTPase
KeywordsSIGNALING PROTEIN/INHIBITOR / GTPase / GDP bound / small molecule inhibitor / covalent binder / SIGNALING PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


forebrain astrocyte development / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / 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 / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / 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 / protein-membrane adaptor activity / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / homeostasis of number of cells within a tissue / positive regulation of glial cell proliferation / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / FRS-mediated FGFR1 signaling / Tie2 Signaling / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / striated muscle cell differentiation / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / Ras activation upon Ca2+ influx through NMDA receptor / FLT3 Signaling / 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 / Insulin receptor signalling cascade / Constitutive Signaling by Overexpressed ERBB2 / small monomeric GTPase / G protein activity / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / regulation of long-term neuronal synaptic plasticity / Signaling by ERBB2 TMD/JMD mutants / 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 / GDP binding / 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 / 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 / Ras protein signal transduction / negative regulation of neuron apoptotic process / mitochondrial outer membrane / 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-21J / GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.571 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
DepositionAug 3, 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 / 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 / _struct_conn.pdbx_leaving_atom_flag / _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

Downloads & links

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Assembly

Deposited unit
A: K-Ras GTPase
B: K-Ras GTPase
C: K-Ras GTPase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,8557
Polymers58,0583
Non-polymers1,7974
Water3,279182
1
A: K-Ras GTPase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,7962
Polymers19,3531
Non-polymers4431
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: K-Ras GTPase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2633
Polymers19,3531
Non-polymers9112
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: K-Ras GTPase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,7962
Polymers19,3531
Non-polymers4431
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)68.333, 84.163, 86.432
Angle α, β, γ (deg.)90.00, 110.95, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-337-

HOH

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Components

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


Mass: 19352.785 Da / Num. of mol.: 3 / 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-GDP / GUANOSINE-5'-DIPHOSPHATE / Guanosine diphosphate


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#3: Chemical ChemComp-21J / N-(1-{[(5,7-dichloro-2,2-dimethyl-1,3-benzodioxol-4-yl)oxy]acetyl}piperidin-4-yl)ethanesulfonamide


Mass: 467.364 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H24Cl2N2O6S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 182 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsTHE SEQUENCE IN THE STRUCTURE REPRESENTS ISOFORM 2B OF GTPASE KRAS. THIS ISOFORM DIFFERS FROM THE ...THE SEQUENCE IN THE STRUCTURE 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: 2 Å3/Da / Density % sol: 38.47 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 31% PEG4000, 0.2M NH4CH3COO, 0.1M Na-citrate, pH 5.6, 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: 0.9999 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 13, 2011
Diffraction measurementDetails: 1.00 degrees, 2.0 sec, detector distance 200.00 mm / Method: \w scans
RadiationMonochromator: Double crystal, Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionAv R equivalents: 0.062 / Number: 233125
ReflectionResolution: 1.57→25 Å / Num. obs: 63323 / % possible obs: 99.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Rmerge(I) obs: 0.062 / Rsym value: 0.062 / Net I/σ(I): 15.212
Reflection shellResolution: 1.57→1.6 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.37 / Mean I/σ(I) obs: 3.429 / Rsym value: 0.37 / % possible all: 99.9
Cell measurementReflection used: 233125

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation2.5 Å25.04 Å
Translation2.5 Å25.04 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
Starting model: PDB ENTRY 3GFT

3gft


Resolution: 1.571→23.516 Å / Occupancy max: 1 / Occupancy min: 0.4 / SU ML: 0.18 / σ(F): 1.35 / Phase error: 24.46 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2017 1996 3.16 %
Rwork0.1834 --
obs0.184 63257 99.42 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 132.2 Å2 / Biso mean: 43.3771 Å2 / Biso min: 15.8 Å2
Refinement stepCycle: LAST / Resolution: 1.571→23.516 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3668 0 113 182 3963
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0073858
X-RAY DIFFRACTIONf_angle_d1.1265234
X-RAY DIFFRACTIONf_chiral_restr0.059596
X-RAY DIFFRACTIONf_plane_restr0.005656
X-RAY DIFFRACTIONf_dihedral_angle_d17.0681435
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 (%)
1.571-1.60990.28991400.24654313445398
1.6099-1.65340.25621430.224944114554100
1.6534-1.70210.2691480.219143724520100
1.7021-1.7570.22631440.202343584502100
1.757-1.81980.28391380.193543664504100
1.8198-1.89260.21991480.19843744522100
1.8926-1.97870.25361370.200744064543100
1.9787-2.0830.20661420.185543784520100
2.083-2.21340.20691440.186343944538100
2.2134-2.38410.20071420.177643924534100
2.3841-2.62380.20561410.184444124553100
2.6238-3.00280.20221430.195344224565100
3.0028-3.78060.20981370.17634379451699
3.7806-23.51820.1661490.16914284443396
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)
14.88840.56342.27297.2294-0.95913.89910.09840.1084-0.1677-0.0557-0.1171-0.43280.18740.38990.03690.16680.04170.0360.31490.00460.189929.140416.8861-12.5988
22.24330.83240.67383.29232.13042.7876-0.04970.10130.0645-0.1803-0.0827-0.3707-0.0730.50220.11960.27450.0418-0.02180.40740.04190.279832.574514.5045-9.243
38.873-2.36021.93574.1041-5.13827.9452-0.00591.10550.3040.1494-0.5497-2.1703-0.48211.20760.48380.7222-0.05890.02220.62750.01990.628429.543813.4412-26.43
42.8025-0.85850.64845.80510.79953.43250.11340.1584-0.2305-0.32-0.06840.32910.15860.07990.01050.1659-0.0006-0.03560.1478-0.00590.175216.939720.6847-17.6328
55.69622.72524.67525.61923.00495.5990.1146-0.3928-0.06420.348-0.11730.25940.0971-0.34950.02470.2183-0.01380.01860.23930.03490.221714.34422.4342-8.6884
68.07724.97594.29173.74454.31277.14420.349-0.084-0.38510.6101-0.2230.09270.7424-0.139-0.05890.28640.0120.00440.22850.01260.256721.33239.8331-7.047
72.817-0.41840.40974.7692-1.33373.5134-0.0146-0.23460.74070.23480.06230.0339-0.76780.1512-0.02170.3416-0.0090.05270.2107-0.04950.35314.723520.970418.5736
88.16584.2648-1.54339.4396-1.23383.62780.267-1.01950.18230.7676-0.13970.235-0.2919-0.1719-0.05980.4130.0847-0.0470.4984-0.0170.51433.431215.739419.6077
96.8205-1.46291.13513.9048-0.26172.46050.08450.2896-0.1414-0.34540.00640.57030.0378-0.1658-0.12210.18980.0017-0.04720.17920.02010.221710.74045.544613.2086
103.9445-0.47231.12635.0338-0.45584.7045-0.05330.14610.2851-0.2730.056-0.2095-0.19780.14760.03360.2051-0.02730.04810.20330.0460.195620.519111.002710.9013
112.1285-0.92013.4494.82430.46056.48130.0806-0.9944-0.71450.57140.014-0.10150.344-0.096-0.20410.2960.01830.02320.56610.16180.3369-0.083329.859542.9085
123.9671.20642.19371.4832-0.31212.85060.1799-1.3048-0.15170.5324-0.10110.1603-0.042-0.31660.00390.338-0.0012-0.01280.58930.08670.30960.614232.860743.5759
135.54280.68662.05436.06933.86396.9869-0.3375-0.65770.4621-0.01430.03240.1897-0.8792-0.28570.27110.3130.0392-0.020.2544-0.02060.1849-2.618242.579134.4378
146.6063.89761.98815.65060.60994.1485-0.24330.3123-0.4635-0.61840.1048-0.4292-0.05960.06410.13530.2408-0.00320.0410.2567-0.01710.24021.512234.206724.8466
157.4174.63045.1568.40996.05918.0780.0288-0.3299-0.51340.44420.2173-0.41090.26030.453-0.24630.23340.0423-0.02960.35280.08820.32467.981830.927538.0455
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 1 through 25 )A0
2X-RAY DIFFRACTION2chain 'A' and (resid 26 through 58 )A0
3X-RAY DIFFRACTION3chain 'A' and (resid 59 through 74 )A0
4X-RAY DIFFRACTION4chain 'A' and (resid 75 through 126 )A0
5X-RAY DIFFRACTION5chain 'A' and (resid 127 through 151 )A0
6X-RAY DIFFRACTION6chain 'A' and (resid 152 through 167 )A0
7X-RAY DIFFRACTION7chain 'B' and (resid 1 through 48 )B0
8X-RAY DIFFRACTION8chain 'B' and (resid 49 through 74 )B0
9X-RAY DIFFRACTION9chain 'B' and (resid 75 through 116 )B0
10X-RAY DIFFRACTION10chain 'B' and (resid 117 through 168 )B0
11X-RAY DIFFRACTION11chain 'C' and (resid 1 through 25 )C0
12X-RAY DIFFRACTION12chain 'C' and (resid 26 through 86 )C0
13X-RAY DIFFRACTION13chain 'C' and (resid 87 through 116 )C0
14X-RAY DIFFRACTION14chain 'C' and (resid 117 through 143 )C0
15X-RAY DIFFRACTION15chain 'C' and (resid 144 through 167 )C0

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