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- PDB-4lyf: Crystal Structure of small molecule vinylsulfonamide 8 covalently... -

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Basic information

Entry
Database: PDB / ID: 4lyf
TitleCrystal Structure of small molecule vinylsulfonamide 8 covalently bound to K-Ras G12C
ComponentsGTPase KRas
KeywordsSIGNALING PROTEIN/INHIBITOR / GTPase / GDP bound / small molecule inhibitor / covalent binder / SIGNALING PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation ...response to mineralocorticoid / GMP binding / forebrain astrocyte development / LRR domain binding / regulation of synaptic transmission, GABAergic / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Rac protein signal transduction / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / myoblast proliferation / skeletal muscle cell differentiation / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / positive regulation of glial cell proliferation / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / cardiac muscle cell proliferation / Signalling to RAS / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Estrogen-stimulated signaling through PRKCZ / glial cell proliferation / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / 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:FGFR4 / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / p38MAPK events / FRS-mediated FGFR1 signaling / Signaling by FGFR3 in disease / protein-membrane adaptor activity / Tie2 Signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / homeostasis of number of cells within a tissue / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Downstream signal transduction / Ras activation upon Ca2+ influx through NMDA receptor / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / response to glucocorticoid / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / small monomeric GTPase / FCERI mediated MAPK activation / liver development / RAF activation / Signaling by ERBB2 TMD/JMD mutants / female pregnancy / Signaling by SCF-KIT / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII / regulation of long-term neuronal synaptic plasticity / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / visual learning / Signaling by ERBB2 KD Mutants / cytoplasmic side of plasma membrane / cytokine-mediated signaling pathway / Regulation of RAS by GAPs / Signaling by CSF1 (M-CSF) in myeloid cells / 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 / positive regulation of cellular senescence / DAP12 signaling / MAPK cascade / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
Similarity search - Function
Small GTPase, Ras-type / Small GTPase Ras domain 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 domain 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-21C / GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.568 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 31, 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 1.3Oct 16, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / 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_entry_details.has_protein_modification / _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: GTPase KRas
B: GTPase KRas
C: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,7987
Polymers58,0583
Non-polymers1,7404
Water3,549197
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)68.265, 83.835, 86.186
Angle α, β, γ (deg.)90.00, 110.90, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-335-

HOH

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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.: 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


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-21C / N-{1-[N-(4,5-dichloro-2-hydroxyphenyl)glycyl]piperidin-4-yl}ethanesulfonamide


Mass: 410.316 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H21Cl2N3O4S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 197 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
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: 1.98 Å3/Da / Density % sol: 38.01 %
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 12, 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: 0.053 / Number: 235812
ReflectionResolution: 1.568→25 Å / Num. obs: 63346 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Rmerge(I) obs: 0.053 / Rsym value: 0.053 / Net I/σ(I): 21.219
Reflection shellResolution: 1.57→1.6 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.368 / Mean I/σ(I) obs: 3.476 / Rsym value: 0.368 / % possible all: 100
Cell measurementReflection used: 235812

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation2.5 Å24.89 Å
Translation2.5 Å24.89 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: 1.568→24.892 Å / Occupancy max: 1 / Occupancy min: 0.16 / SU ML: 0.15 / σ(F): 1.33 / Phase error: 20.21 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1922 2006 3.17 %
Rwork0.1693 --
obs0.17 63330 99.75 %
Solvent computationShrinkage radii: 1 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 101.84 Å2 / Biso mean: 38.1973 Å2 / Biso min: 14.7 Å2
Refinement stepCycle: LAST / Resolution: 1.568→24.892 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3701 0 109 197 4007
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0083875
X-RAY DIFFRACTIONf_angle_d1.1815249
X-RAY DIFFRACTIONf_chiral_restr0.059598
X-RAY DIFFRACTIONf_plane_restr0.005657
X-RAY DIFFRACTIONf_dihedral_angle_d17.0171436
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 (%)
1.568-1.60720.23381400.21634313445398
1.6072-1.65070.27681360.204143974533100
1.6507-1.69930.24321410.195443704511100
1.6993-1.75410.21941410.184443764517100
1.7541-1.81680.20081420.181943464488100
1.8168-1.88950.20041480.184243814529100
1.8895-1.97540.22021430.179343724515100
1.9754-2.07950.21271480.171343874535100
2.0795-2.20980.21111350.174743824517100
2.2098-2.38030.18471470.166543754522100
2.3803-2.61960.20391440.171844034547100
2.6196-2.99810.20581490.179444044553100
2.9981-3.77510.19371450.164243964541100
3.7751-24.89520.15751470.15474422456999
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)
13.99850.46591.74244.111-0.56043.36060.1235-0.0443-0.2319-0.0123-0.0869-0.42320.29540.34640.00130.14870.03840.02330.2884-0.00370.169929.006917.5847-12.5287
21.460.62730.79383.10571.26882.12090.03130.09080.0212-0.1183-0.1337-0.3152-0.00190.48340.11160.24820.0452-0.01140.42950.01140.268332.434315.277-9.2354
33.0094-0.06-0.42033.48881.25452.96220.05120.5433-0.1497-0.78420.1465-0.72960.25580.6123-0.21250.4380.04490.02780.3837-0.04710.339526.330115.3133-22.658
42.539-1.09690.33218.01692.49912.90980.21030.3744-0.3356-0.7307-0.05790.26540.1070.1907-0.08530.25610.0362-0.06650.2148-0.04430.193115.768922.0738-22.0467
53.2002-0.55390.61263.40840.03973.01410.06050.0375-0.1754-0.14280.01810.27810.10.0017-0.05070.1677-0.0167-0.01740.1670.01850.165316.54822.3147-13.5356
66.38171.52762.41244.28320.98682.56280.0606-0.51830.06640.2264-0.11550.2664-0.0089-0.2770.04210.2236-0.0120.00720.2410.01880.199114.246223.1135-8.562
76.49082.14690.38262.4762.76067.3820.2158-0.012-0.61660.6075-0.16540.20450.7825-0.212-0.04220.30380.0113-0.01120.26180.01010.302521.040310.4573-6.9198
83.2598-0.71610.32994.6116-0.21922.98610.0496-0.24970.53070.00920.06710.3693-0.5121-0.1381-0.07740.26090.0250.04970.1826-0.02240.28413.186119.088718.7439
92.3421-2.33360.92582.3562-1.28473.62290.1965-0.25330.4950.28830.036-0.0717-0.5785-0.3255-0.19840.5247-0.12250.15830.3562-0.03790.605516.800126.145417.8845
103.68580.0857-0.52165.2129-1.44063.24990.1641-0.2571-0.18910.2154-0.10670.5736-0.2575-0.2097-0.12010.29520.0594-0.02790.3387-0.03450.49293.415816.161619.3668
113.1555-0.5482-0.38963.82730.11591.57330.1310.2717-0.087-0.4441-0.09390.69330.0241-0.2776-0.06680.17490.0204-0.05450.18820.00370.221811.00946.294713.2184
122.6035-0.23310.5674.6416-0.04593.11030.02760.13070.2248-0.2931-0.0506-0.3057-0.1750.13650.02430.21130.0020.05820.19380.03990.177621.014111.565711.3649
133.2032-0.4831.14163.88060.02144.68440.1143-0.561-0.39830.4803-0.1618-0.16030.3170.09710.02570.27830.0080.0120.36180.09740.2406-0.500130.480642.522
140.35750.37091.14930.57181.04813.98830.02270.1995-0.47270.16530.0217-0.11350.41950.24090.01090.4630.0296-0.02680.57680.24310.56365.213325.331845.366
152.20641.58560.94935.5519-1.05174.4980.1364-0.99740.28460.6739-0.06360.8248-0.356-0.4792-0.03830.49560.01330.05960.5982-0.02580.4233-2.937938.577747.4301
163.82931.38611.90095.10021.62326.6168-0.0928-0.28250.332-0.0471-0.05820.3567-0.6162-0.21960.15450.19850.01580.01760.1933-0.00020.1754-4.790641.029733.3058
174.03290.6611-0.69973.5253-2.3462.9442-0.05380.0929-0.1822-0.2401-0.0586-0.1640.0529-0.14790.10780.12120.0196-0.00090.20010.01990.1383-0.082934.678530.0024
185.82643.35062.66957.64854.79433.2113-0.52770.87780.0248-0.83740.3947-0.6166-0.46750.53390.18580.3126-0.05070.04190.26690.01910.20853.781640.501923.6847
194.71533.6974-0.6153.4925-1.80123.0056-0.0153-0.0545-0.6937-0.1696-0.1149-0.51020.39370.18720.11070.180.03330.01170.18850.0230.32684.024828.252331.6176
207.82882.16931.40542.53893.31034.6826-0.2329-0.279-0.10850.32020.1938-0.6958-0.250.4707-0.01960.3021-0.0019-0.09650.36870.08410.340910.587635.570440.157
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 83 )A0
4X-RAY DIFFRACTION4chain 'A' and (resid 84 through 103 )A0
5X-RAY DIFFRACTION5chain 'A' and (resid 104 through 126 )A0
6X-RAY DIFFRACTION6chain 'A' and (resid 127 through 151 )A0
7X-RAY DIFFRACTION7chain 'A' and (resid 152 through 167 )A0
8X-RAY DIFFRACTION8chain 'B' and (resid 1 through 25 )B0
9X-RAY DIFFRACTION9chain 'B' and (resid 26 through 48 )B0
10X-RAY DIFFRACTION10chain 'B' and (resid 49 through 74 )B0
11X-RAY DIFFRACTION11chain 'B' and (resid 75 through 116 )B0
12X-RAY DIFFRACTION12chain 'B' and (resid 117 through 167 )B0
13X-RAY DIFFRACTION13chain 'C' and (resid 2 through 25 )C0
14X-RAY DIFFRACTION14chain 'C' and (resid 26 through 48 )C0
15X-RAY DIFFRACTION15chain 'C' and (resid 49 through 76 )C0
16X-RAY DIFFRACTION16chain 'C' and (resid 77 through 104 )C0
17X-RAY DIFFRACTION17chain 'C' and (resid 105 through 126 )C0
18X-RAY DIFFRACTION18chain 'C' and (resid 127 through 137 )C0
19X-RAY DIFFRACTION19chain 'C' and (resid 138 through 151 )C0
20X-RAY DIFFRACTION20chain 'C' and (resid 152 through 167 )C0

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