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- PDB-6b0v: Crystal Structure of small molecule ARS-107 covalently bound to K... -

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Basic information

Entry
Database: PDB / ID: 6b0v
TitleCrystal Structure of small molecule ARS-107 covalently bound to K-Ras G12C
ComponentsGTPase KRas
KeywordsSIGNALING PROTEIN / 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 / 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-C8G / GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.29 Å
AuthorsHansen, R. / Peters, U. / Babbar, A. / Chen, Y. / Feng, J. / Janes, M.R. / Li, L.-S. / Ren, P. / Liu, Y. / Zarrinkar, P.P.
CitationJournal: Nat. Struct. Mol. Biol. / Year: 2018
Title: The reactivity-driven biochemical mechanism of covalent KRASG12Cinhibitors.
Authors: Hansen, R. / Peters, U. / Babbar, A. / Chen, Y. / Feng, J. / Janes, M.R. / Li, L.S. / Ren, P. / Liu, Y. / Zarrinkar, P.P.
History
DepositionSep 15, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 16, 2018Provider: repository / Type: Initial release
Revision 1.1May 30, 2018Group: Data collection / Database references / Source and taxonomy
Category: citation / citation_author / entity_src_gen
Item: _citation.journal_abbrev / _citation.pdbx_database_id_PubMed ..._citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name / _entity_src_gen.pdbx_host_org_strain
Revision 1.2Nov 7, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
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_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_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_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_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.ptnr2_symmetry

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,58310
Polymers38,7062
Non-polymers1,8778
Water7,242402
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2915
Polymers19,3531
Non-polymers9394
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2915
Polymers19,3531
Non-polymers9394
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)33.140, 39.880, 62.430
Angle α, β, γ (deg.)77.000, 81.240, 77.580
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 19352.785 Da / Num. of mol.: 2 / Fragment: UNP residues 1-169 / Mutation: G12C, C51S, C80L, C118S
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
#2: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
#3: Chemical ChemComp-C8G / 1-[3-(4-{[(4,5-dichloro-2-hydroxyphenyl)amino]acetyl}piperazin-1-yl)azetidin-1-yl]propan-1-one


Mass: 415.314 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H24Cl2N4O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 402 / 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: 2.02 Å3/Da / Density % sol: 39 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 29% PEG 4000, 0.2 M CaCl2, 0.1 M Tris pH=8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.2 / Wavelength: 0.999995 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Aug 14, 2013
RadiationMonochromator: Double-crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999995 Å / Relative weight: 1
ReflectionResolution: 1.29→32.171 Å / Num. obs: 68823 / % possible obs: 90.4 % / Redundancy: 2.8 % / Rpim(I) all: 0.059 / Rrim(I) all: 0.104 / Rsym value: 0.085 / Net I/av σ(I): 4.1 / Net I/σ(I): 6.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) allRsym value% possible all
1.29-1.3630.341297160.2340.4150.34187.5
1.36-1.442.90.2412.892710.1670.2940.24187.7
1.44-1.542.90.173.886830.1190.2080.1788.1
1.54-1.672.80.126582460.0890.1550.12689.6
1.67-1.822.80.1035.977350.0730.1270.10391.2
1.82-2.042.80.0916.271110.0660.1130.09193.4
2.04-2.362.80.0886.963570.0620.1080.08893.7
2.36-2.882.60.0797.653740.0580.0990.07994
2.88-4.082.90.078.141770.0490.0860.0795.1
4.08-32.1713.10.073821530.0490.0880.07389.7

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation4.65 Å32.17 Å
Translation4.65 Å32.17 Å

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Processing

Software
NameVersionClassification
iMOSFLMdata collection
SCALA3.3.21data scaling
PHASER2.5.6phasing
REFMAC5.8.0073refinement
PDB_EXTRACT3.22data extraction
iMOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5F2E

5f2e


Resolution: 1.29→32.171 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.947 / SU B: 2.292 / SU ML: 0.048 / SU R Cruickshank DPI: 0.0617 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.062 / ESU R Free: 0.066
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2183 3371 4.9 %RANDOM
Rwork0.1824 ---
obs0.1841 65427 90.39 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 51.87 Å2 / Biso mean: 15.999 Å2 / Biso min: 6.16 Å2
Baniso -1Baniso -2Baniso -3
1-0.06 Å2-0.38 Å20.38 Å2
2--0.92 Å21.08 Å2
3----0.66 Å2
Refinement stepCycle: final / Resolution: 1.29→32.171 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2642 0 114 435 3191
Biso mean--13.99 25.29 -
Num. residues----334
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0230.0192886
X-RAY DIFFRACTIONr_bond_other_d0.0010.022709
X-RAY DIFFRACTIONr_angle_refined_deg2.4782.0043932
X-RAY DIFFRACTIONr_angle_other_deg2.1993.0016242
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.845355
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.07924.485136
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.73515501
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.6811519
X-RAY DIFFRACTIONr_chiral_restr0.1350.2439
X-RAY DIFFRACTIONr_gen_planes_refined0.0150.023264
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02653
LS refinement shellResolution: 1.29→1.323 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.27 237 -
Rwork0.272 4699 -
all-4936 -
obs--87.55 %
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)
10.7404-0.035-0.06530.0953-0.23150.8196-0.03860.0260.00540.0033-0.0073-0.02510.0062-0.00330.04590.008-0.00550.00310.007-0.00030.0108-18.2369.8636.664
20.1792-0.0610.13750.3481-0.21870.6153-0.002-0.01820.0236-0.0192-0.0082-0.00610.0358-0.01810.01020.0056-0.0023-0.00090.01880.00550.0077-2.055-2.51734.946
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 167
2X-RAY DIFFRACTION1A201 - 204
3X-RAY DIFFRACTION2B1 - 167
4X-RAY DIFFRACTION2B201 - 204

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