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- PDB-5v9u: Crystal Structure of small molecule ARS-1620 covalently bound to ... -

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Basic information

Entry
Database: PDB / ID: 5v9u
TitleCrystal Structure of small molecule ARS-1620 covalently bound to K-Ras G12C
ComponentsGTPase KRas
KeywordsHYDROLASE/HYDROLASE INHIBITOR / small GTPase domain / covalent inhibitor bound / switch II pocket / GDP bound / HYDROLASE-HYDROLASE INHIBITOR complex
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-91S / GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.38 Å
AuthorsJanes, M.R. / Zhang, J. / Li, L.-S. / Hansen, R. / Peters, U. / Guo, X. / Chen, Y. / Babbar, A. / Firdaus, S.J. / Feng, J. ...Janes, M.R. / Zhang, J. / Li, L.-S. / Hansen, R. / Peters, U. / Guo, X. / Chen, Y. / Babbar, A. / Firdaus, S.J. / Feng, J. / Chen, J.H. / Li, S. / Brehmer, D. / Darjania, L. / Li, S. / Long, Y.O. / Thach, C. / Liu, Y. / Zarieh, A. / Ely, T. / Kucharski, J.M. / Kessler, L.V. / Wu, T. / Wang, Y. / Yao, Y. / Deng, X. / Zarrinkar, P. / Dashyant, D. / Lorenzi, M.V. / Hu-Lowe, D. / Patricelli, M.P. / Ren, P. / Liu, Y.
CitationJournal: Cell / Year: 2018
Title: Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor.
Authors: Janes, M.R. / Zhang, J. / Li, L.S. / Hansen, R. / Peters, U. / Guo, X. / Chen, Y. / Babbar, A. / Firdaus, S.J. / Darjania, L. / Feng, J. / Chen, J.H. / Li, S. / Li, S. / Long, Y.O. / Thach, ...Authors: Janes, M.R. / Zhang, J. / Li, L.S. / Hansen, R. / Peters, U. / Guo, X. / Chen, Y. / Babbar, A. / Firdaus, S.J. / Darjania, L. / Feng, J. / Chen, J.H. / Li, S. / Li, S. / Long, Y.O. / Thach, C. / Liu, Y. / Zarieh, A. / Ely, T. / Kucharski, J.M. / Kessler, L.V. / Wu, T. / Yu, K. / Wang, Y. / Yao, Y. / Deng, X. / Zarrinkar, P.P. / Brehmer, D. / Dhanak, D. / Lorenzi, M.V. / Hu-Lowe, D. / Patricelli, M.P. / Ren, P. / Liu, Y.
History
DepositionMar 23, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 7, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 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_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_alt_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.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_alt_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_alt_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.ptnr3_symmetry / _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.pdbx_ptnr1_label_alt_id / _struct_conn.pdbx_ptnr2_label_alt_id / _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_label_seq_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)41,06716
Polymers38,7062
Non-polymers2,36114
Water6,864381
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4818
Polymers19,3531
Non-polymers1,1287
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,5858
Polymers19,3531
Non-polymers1,2327
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)33.440, 39.740, 61.780
Angle α, β, γ (deg.)77.480, 81.970, 77.200
Int Tables number1
Space group name H-MP1

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 19352.785 Da / Num. of mol.: 2 / 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 , 5 types, 395 molecules

#2: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Ca
#3: Chemical ChemComp-91S / (S)-1-{4-[6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl] piperazin-1-yl}propan-1-one


Mass: 432.851 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H19ClF2N4O2
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE / Guanosine diphosphate


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


Mass: 18.015 Da / Num. of mol.: 381 / Source method: isolated from a natural source / Formula: H2O

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Details

Nonpolymer detailsLIGAND 91S IS A CHIRAL ENTITY (ATROPISOMER). THE COMPOUND IS A STABLE S-ISOMER AND INTERCONVERSION ...LIGAND 91S IS A CHIRAL ENTITY (ATROPISOMER). THE COMPOUND IS A STABLE S-ISOMER AND INTERCONVERSION IN SOLUTION FOR SEVERAL WEEKS AT 37C IS NOT SEEN FOR THIS CLASS OF COMPOUND

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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: 2.01 Å3/Da / Density % sol: 38.8 %
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: 5.0.3 / Wavelength: 0.976484 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 18, 2016
RadiationMonochromator: Si(220) cylindrically bent single crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976484 Å / Relative weight: 1
ReflectionResolution: 1.38→60.031 Å / Num. obs: 58567 / % possible obs: 94.5 % / Redundancy: 2.2 % / Rpim(I) all: 0.041 / Rrim(I) all: 0.064 / Rsym value: 0.049 / Net I/av σ(I): 9.9 / Net I/σ(I): 10.3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsRpim(I) allRrim(I) allRsym value% possible all
1.38-1.452.10.332.30.280.4340.3391.1
1.45-1.542.30.2213.40.1860.290.22193.5
1.54-1.652.30.1554.80.1290.2020.15593.9
1.65-1.782.30.116.80.0910.1430.1194.3
1.78-1.952.30.06910.50.0580.090.06995.2
1.95-2.182.30.04615.40.0390.0610.04695.8
2.18-2.522.20.03817.40.0310.0490.03896.2
2.52-3.092.20.03616.30.030.0470.03696.5
3.09-4.362.20.03417.50.0280.0450.03497
4.36-38.0282.30.02522.70.0210.0330.02596.3

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation4.55 Å38.03 Å
Translation4.55 Å38.03 Å

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Processing

Software
NameVersionClassification
SCALA3.3.21data scaling
PHASER2.5.6phasing
REFMAC5.8.0073refinement
PDB_EXTRACT3.22data extraction
MOSFLM7.2.0data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5f2e

5f2e


Resolution: 1.38→60.03 Å / Cor.coef. Fo:Fc: 0.975 / Cor.coef. Fo:Fc free: 0.963 / SU B: 2.363 / SU ML: 0.046 / SU R Cruickshank DPI: 0.061 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.061 / ESU R Free: 0.067 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1893 2888 4.9 %RANDOM
Rwork0.1494 ---
obs0.1513 55678 94.47 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 51.17 Å2 / Biso mean: 16.153 Å2 / Biso min: 3.8 Å2
Baniso -1Baniso -2Baniso -3
1--0.17 Å2-0.12 Å20.08 Å2
2--0.28 Å20.27 Å2
3----0.06 Å2
Refinement stepCycle: final / Resolution: 1.38→60.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2653 0 148 428 3229
Biso mean--9.36 26.04 -
Num. residues----336
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0250.0193075
X-RAY DIFFRACTIONr_bond_other_d0.0010.022872
X-RAY DIFFRACTIONr_angle_refined_deg2.4772.0124216
X-RAY DIFFRACTIONr_angle_other_deg2.1883.0016639
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9755395
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.7524.49147
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.59315539
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.3251521
X-RAY DIFFRACTIONr_chiral_restr0.1460.2467
X-RAY DIFFRACTIONr_gen_planes_refined0.0150.023518
X-RAY DIFFRACTIONr_gen_planes_other0.0040.02703
LS refinement shellResolution: 1.38→1.416 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.262 200 -
Rwork0.264 3929 -
all-4129 -
obs--90.27 %
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)
11.09580.03060.15220.6003-0.0540.8744-0.04840.07340.0135-0.02490.017-0.01120.01080.02040.03130.00540.00590.00720.05020.03310.0244-18.08349.78997.0448
20.58130.1153-0.18930.7067-0.21250.8435-0.0239-0.03080.00990.0167-0.005-0.0090.0159-0.00710.02890.00210.00520.00190.10570.05080.0276-2.2395-2.331535.1859
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 169
2X-RAY DIFFRACTION2B2 - 168

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