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- PDB-6tam: X-RAY STRUCTURE OF HUMAN K-RAS G12C IN COMPLEX WITH COVALENT ISOQ... -

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Basic information

Entry
Database: PDB / ID: 6tam
TitleX-RAY STRUCTURE OF HUMAN K-RAS G12C IN COMPLEX WITH COVALENT ISOQUINOLINONE INHIBITOR (COMPOUND 3)
ComponentsGTPase KRas
KeywordsHYDROLASE / KRAS / INHIBITOR / COVALENT BINDING
Function / homology
Function and homology information


GMP binding / response to mineralocorticoid / forebrain astrocyte development / LRR domain binding / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis ...GMP binding / response to mineralocorticoid / forebrain astrocyte development / LRR domain binding / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / 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 / 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 / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / protein-membrane adaptor activity / Signaling by FGFR3 in disease / p38MAPK events / FRS-mediated FGFR1 signaling / Tie2 Signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / positive regulation of glial cell proliferation / 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 / SHC1 events in ERBB2 signaling / Insulin receptor signalling cascade / 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 / female pregnancy / RAF activation / liver development / Signaling by ERBB2 TMD/JMD mutants / Signaling by high-kinase activity BRAF mutants / regulation of long-term neuronal synaptic plasticity / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / visual learning / Signaling by ERBB2 KD Mutants / Signaling by CSF1 (M-CSF) in myeloid cells / RAS processing / Regulation of RAS by GAPs / Negative regulation of MAPK pathway / cytoplasmic side of plasma membrane / cytokine-mediated signaling 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 / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / positive regulation of cellular senescence / MAPK cascade / DAP12 signaling
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
GUANOSINE-5'-DIPHOSPHATE / Chem-MZQ / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.64 Å
AuthorsFriberg, A. / Nguyen, D.
CitationJournal: Chemmedchem / Year: 2020
Title: Computationally Empowered Workflow Identifies Novel Covalent Allosteric Binders for KRASG12C.
Authors: Mortier, J. / Friberg, A. / Badock, V. / Moosmayer, D. / Schroeder, J. / Steigemann, P. / Siegel, F. / Gradl, S. / Bauser, M. / Hillig, R.C. / Briem, H. / Eis, K. / Bader, B. / Nguyen, D. / Christ, C.D.
History
DepositionOct 30, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 8, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 15, 2020Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Jun 3, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Nov 13, 2024Group: Advisory / Data collection ...Advisory / 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 / pdbx_struct_conn_angle / pdbx_unobs_or_zero_occ_atoms / struct_conn
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 / _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)20,2034
Polymers19,3531
Non-polymers8503
Water2,252125
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area870 Å2
ΔGint-19 kcal/mol
Surface area8310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.144, 58.522, 66.141
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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.: 1 / Mutation: G12C, C51S, C80L, C118S
Source method: isolated from a genetically manipulated source
Details: Protein covalently modified at G12C / Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli K-12 (bacteria) / References: UniProt: P01116
#2: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-MZQ / 7-[2,4-bis(fluoranyl)phenyl]-3-[(3~{R})-1-propanoylpyrrolidin-3-yl]-4~{H}-isoquinolin-1-one


Mass: 382.403 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H20F2N2O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 125 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY
Nonpolymer detailsFIRST CRYSTAL STRUCTURE IN THE ISOQUINOLINONE SERIES. SWITCH II CONFORMATION ONLY TO BE ANALYZED ...FIRST CRYSTAL STRUCTURE IN THE ISOQUINOLINONE SERIES. SWITCH II CONFORMATION ONLY TO BE ANALYZED WITH CAUTION, DENSITY HERE IS VERY WEAK (I.E. HIGH B-FACTORS). COMPOUND IS WELL-DEFINED BY ELECTRON DENSITY. CORE IN COMPLETELY DIFFERENT ORIENTATION THAN THAT OF ARS-COMPOUNDS. AMIDE OF ISOQUINOLINONE EXHIBIT TWO HYDROGEN BONDS TO THE BACKBONE OF GLY10. TERMINAL PHENYL GROUP IN A SIMILAR POSITION AS FOUND IN ARS-1620.

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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: 2.06 Å3/Da / Density % sol: 40.21 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.9 / Details: 100 mM MES pH 6.9 and 34% PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 16, 2018
RadiationMonochromator: KMC-1 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.64→50 Å / Num. obs: 20063 / % possible obs: 99.2 % / Redundancy: 12.8 % / Biso Wilson estimate: 34.2 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.0071 / Net I/σ(I): 20.1
Reflection shellResolution: 1.64→1.74 Å / Redundancy: 11.8 % / Mean I/σ(I) obs: 2.17 / Num. unique obs: 3072 / CC1/2: 0.818 / Rrim(I) all: 0.991 / % possible all: 95.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.64→43.83 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.963 / SU B: 4.198 / SU ML: 0.07 / Cross valid method: THROUGHOUT / ESU R: 0.102 / ESU R Free: 0.096 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20053 1001 5 %RANDOM
Rwork0.1742 ---
obs0.17549 19061 99.23 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 27.391 Å2
Baniso -1Baniso -2Baniso -3
1--0.2 Å2-0 Å2-0 Å2
2---0.64 Å20 Å2
3---0.83 Å2
Refinement stepCycle: LAST / Resolution: 1.64→43.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1359 0 57 125 1541
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0131478
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171338
X-RAY DIFFRACTIONr_angle_refined_deg1.4761.7142013
X-RAY DIFFRACTIONr_angle_other_deg1.3541.6173114
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1745179
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.01223.07778
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.95615260
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.568159
X-RAY DIFFRACTIONr_chiral_restr0.0640.2193
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.021669
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02306
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.9872.157704
X-RAY DIFFRACTIONr_mcbond_other0.9882.157703
X-RAY DIFFRACTIONr_mcangle_it1.7073.232887
X-RAY DIFFRACTIONr_mcangle_other1.7063.232888
X-RAY DIFFRACTIONr_scbond_it1.1842.365774
X-RAY DIFFRACTIONr_scbond_other1.1852.364773
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.9133.4781127
X-RAY DIFFRACTIONr_long_range_B_refined4.626.1281708
X-RAY DIFFRACTIONr_long_range_B_other4.54725.751690
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.64→1.682 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.269 70 -
Rwork0.29 1247 -
obs--89.59 %
Refinement TLS params.Method: refined / Origin x: 7.0484 Å / Origin y: 0.4969 Å / Origin z: 6.8961 Å
111213212223313233
T0.0077 Å20.0123 Å20.001 Å2-0.0606 Å20.0038 Å2--0.0006 Å2
L1.061 °2-0.102 °2-0.0985 °2-1.3886 °2-0.2631 °2--1.5427 °2
S0.0501 Å °0.0497 Å °-0.0033 Å °-0.0273 Å °-0.0627 Å °-0.0222 Å °0.075 Å °0.025 Å °0.0125 Å °

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