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- PDB-5f2e: Crystal Structure of small molecule ARS-853 covalently bound to K... -

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Basic information

Entry
Database: PDB / ID: 5f2e
TitleCrystal Structure of small molecule ARS-853 covalently bound to K-Ras G12C
ComponentsGTPase KRas
KeywordsHYDROLASE / small GTPase domain / covalent inhibitor bound / switch II pocket / GDP bound
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-5UT / GUANOSINE-5'-DIPHOSPHATE / GLYCINE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.4 Å
AuthorsPatricelli, M.P. / Janes, M.R. / Li, L.-S. / Hansen, R. / Peters, U. / Kessler, L.V. / Chen, Y. / Kucharski, J.M. / Feng, J. / Ely, T. ...Patricelli, M.P. / Janes, M.R. / Li, L.-S. / Hansen, R. / Peters, U. / Kessler, L.V. / Chen, Y. / Kucharski, J.M. / Feng, J. / Ely, T. / Chen, J.H. / Firdaus, S.J. / Babbar, A. / Ren, P. / Liu, Y.
CitationJournal: Cancer Discov / Year: 2016
Title: Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State.
Authors: Patricelli, M.P. / Janes, M.R. / Li, L.S. / Hansen, R. / Peters, U. / Kessler, L.V. / Chen, Y. / Kucharski, J.M. / Feng, J. / Ely, T. / Chen, J.H. / Firdaus, S.J. / Babbar, A. / Ren, P. / Liu, Y.
History
DepositionDec 1, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 13, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 16, 2016Group: Database references
Revision 1.2Nov 22, 2017Group: Derived calculations / Refinement description / Category: pdbx_struct_oper_list / software
Item: _pdbx_struct_oper_list.symmetry_operation / _software.classification
Revision 1.3Sep 27, 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)20,5127
Polymers19,3531
Non-polymers1,1606
Water3,225179
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1280 Å2
ΔGint-20 kcal/mol
Surface area8090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.110, 43.080, 93.960
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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 / Fragment: GTPase domain
Mutation: G12C, C51S, C80L, C118S, R151G, E153D, Q165K, Y166H, R167K, L168E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Plasmid: pJexpress411 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P01116

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Non-polymers , 6 types, 185 molecules

#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#3: 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
#4: Chemical ChemComp-5UT / 1-[3-[4-[2-[[4-chloranyl-5-(1-methylcyclopropyl)-2-oxidanyl-phenyl]amino]ethanoyl]piperazin-1-yl]azetidin-1-yl]prop-2-en-1-one


Mass: 432.944 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H29ClN4O3
#5: Chemical ChemComp-GLY / GLYCINE / Glycine


Type: peptide linking / Mass: 75.067 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H5NO2
#6: 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
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 179 / 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: 2.05 Å3/Da / Density % sol: 39.85 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 10.5
Details: 2.2 M 3:2 NaH2PO4/K2HPO4, 0.2 M Li2SO4, 0.1 M glycine pH=10.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.977408 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 5, 2014
RadiationMonochromator: Si(220) Asymmetric cut single crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.977408 Å / Relative weight: 1
ReflectionResolution: 1.4→46.98 Å / Num. all: 31261 / Num. obs: 31261 / % possible obs: 97.6 % / Redundancy: 4 % / Rpim(I) all: 0.035 / Rrim(I) all: 0.073 / Rsym value: 0.063 / Net I/av σ(I): 7.908 / Net I/σ(I): 12.5 / Num. measured all: 124584
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym valueNet I/σ(I) obs% possible all
1.4-1.482.90.3072.51137038550.2150.3073.385.6
1.48-1.5740.2323.21718243370.1310.2325.498.9
1.57-1.674.20.1714.41729540790.0940.1717.499.9
1.67-1.814.20.126.31629138430.0650.129.7100
1.81-1.984.20.0848.61494935380.0460.08413.299.9
1.98-2.214.20.05811.91359132290.0320.05817.299.9
2.21-2.564.20.05112.81192628690.0280.05119.399.9
2.56-3.134.10.0639.1996624380.0350.06321.699.7
3.13-4.433.90.04513.4745019310.0250.0452599.5
4.43-36.10740.02523.9456411420.0140.02524.699.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
iMOSFLMdata reduction
SCALA3.3.21data scaling
PHASER2.5.5phasing
REFMACrefinement
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4LUC

4luc


Resolution: 1.4→46.98 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.965 / WRfactor Rfree: 0.1745 / WRfactor Rwork: 0.1479 / FOM work R set: 0.8911 / SU B: 1.968 / SU ML: 0.038 / SU R Cruickshank DPI: 0.0595 / SU Rfree: 0.061 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.059 / ESU R Free: 0.061 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1759 1583 5.1 %RANDOM
Rwork0.1503 ---
obs0.1516 29624 97.37 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 56.27 Å2 / Biso mean: 13.079 Å2 / Biso min: 4.62 Å2
Baniso -1Baniso -2Baniso -3
1-0.03 Å2-0 Å20 Å2
2---0.01 Å2-0 Å2
3----0.02 Å2
Refinement stepCycle: final / Resolution: 1.4→46.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1336 0 81 187 1604
Biso mean--10.42 23.37 -
Num. residues----168
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0250.0191578
X-RAY DIFFRACTIONr_bond_other_d0.0010.021489
X-RAY DIFFRACTIONr_angle_refined_deg2.6262.0142161
X-RAY DIFFRACTIONr_angle_other_deg1.1113.0013451
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9065201
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.24224.47476
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.49615279
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.4711511
X-RAY DIFFRACTIONr_chiral_restr0.1580.2238
X-RAY DIFFRACTIONr_gen_planes_refined0.0170.021806
X-RAY DIFFRACTIONr_gen_planes_other0.0060.02356
X-RAY DIFFRACTIONr_mcbond_it1.1170.798734
X-RAY DIFFRACTIONr_mcbond_other1.1040.798729
X-RAY DIFFRACTIONr_mcangle_it1.7391.196929
LS refinement shellResolution: 1.4→1.436 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.284 87 -
Rwork0.231 1752 -
all-1839 -
obs--78.59 %
Refinement TLS params.Method: refined / Origin x: 17.924 Å / Origin y: -1.6678 Å / Origin z: -12.4812 Å
111213212223313233
T0.0048 Å2-0.0019 Å2-0.0045 Å2-0.0045 Å2-0.0007 Å2--0.0078 Å2
L0.3959 °2-0.0188 °2-0.0947 °2-0.3727 °2-0.0269 °2--0.6683 °2
S-0.0089 Å °0.0118 Å °0.0255 Å °0.0186 Å °-0.009 Å °-0.0028 Å °-0.0341 Å °0.0119 Å °0.0179 Å °

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