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- PDB-6n2j: Tetrahydropyridopyrimidines as Covalent Inhibitors of KRAS-G12C -

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Basic information

Entry
Database: PDB / ID: 6n2j
TitleTetrahydropyridopyrimidines as Covalent Inhibitors of KRAS-G12C
ComponentsGTPase KRas
KeywordsONCOPROTEIN / KRAS proto-oncogene / GTPase
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 / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / 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 / p38MAPK events / Tie2 Signaling / FRS-mediated FGFR1 signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / 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 / 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 / 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
GUANOSINE-5'-DIPHOSPHATE / Chem-K9M / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.8 Å
AuthorsVigers, G.P.
CitationJournal: ACS Med Chem Lett / Year: 2018
Title: Discovery of Tetrahydropyridopyrimidines as Irreversible Covalent Inhibitors of KRAS-G12C with In Vivo Activity.
Authors: Fell, J.B. / Fischer, J.P. / Baer, B.R. / Ballard, J. / Blake, J.F. / Bouhana, K. / Brandhuber, B.J. / Briere, D.M. / Burgess, L.E. / Burkard, M.R. / Chiang, H. / Chicarelli, M.J. / ...Authors: Fell, J.B. / Fischer, J.P. / Baer, B.R. / Ballard, J. / Blake, J.F. / Bouhana, K. / Brandhuber, B.J. / Briere, D.M. / Burgess, L.E. / Burkard, M.R. / Chiang, H. / Chicarelli, M.J. / Davidson, K. / Gaudino, J.J. / Hallin, J. / Hanson, L. / Hee, K. / Hicken, E.J. / Hinklin, R.J. / Marx, M.A. / Mejia, M.J. / Olson, P. / Savechenkov, P. / Sudhakar, N. / Tang, T.P. / Vigers, G.P. / Zecca, H. / Christensen, J.G.
History
DepositionNov 13, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 12, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 23, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Oct 11, 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

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Assembly

Deposited unit
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2224
Polymers19,3531
Non-polymers8693
Water2,198122
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)40.250, 51.130, 90.120
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli (E. coli) / 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-K9M / 1-{4-[7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl}propan-1-one


Mass: 401.504 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H27N5O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 122 / 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: 2.4 Å3/Da / Density % sol: 48.66 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 0.1M Na Citrate, pH 5.0 29% PEG8000 0.2M Amm Acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E / Wavelength: 1.5418 Å
DetectorType: DECTRIS PILATUS3 X 1M / Detector: PIXEL / Date: Oct 1, 2015 / Details: Osmic mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.8→30 Å / Num. obs: 17680 / % possible obs: 99 % / Redundancy: 4.76 % / Rmerge(I) obs: 0.056 / Rpim(I) all: 0.046 / Rrim(I) all: 0.1019 / Net I/σ(I): 11.22
Reflection shellResolution: 1.8→1.9 Å / Redundancy: 4.2 % / Rmerge(I) obs: 0.259 / Mean I/σ(I) obs: 2.9 / Num. unique obs: 2300 / Rpim(I) all: 0.135 / Rrim(I) all: 0.293 / % possible all: 99

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
REFMAC5.8.0238refinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4LYJ

4lyj


Resolution: 1.8→29.84 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.935 / SU B: 5.768 / SU ML: 0.08 / SU R Cruickshank DPI: 0.1692 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.169 / ESU R Free: 0.113
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2037 842 4.8 %RANDOM
Rwork0.1299 ---
obs0.1335 16794 98.69 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 92.5 Å2 / Biso mean: 29.19 Å2 / Biso min: 17.85 Å2
Baniso -1Baniso -2Baniso -3
1--0.45 Å2-0 Å2-0 Å2
2--0.16 Å2-0 Å2
3---0.29 Å2
Refinement stepCycle: final / Resolution: 1.8→29.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1347 0 59 122 1528
Biso mean--24.87 39.76 -
Num. residues----168
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0131433
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171283
X-RAY DIFFRACTIONr_angle_refined_deg1.8951.7181941
X-RAY DIFFRACTIONr_angle_other_deg1.4821.5982978
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2925167
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.55222.65879
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.49515252
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.691510
X-RAY DIFFRACTIONr_chiral_restr0.0860.2185
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.021586
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02289
X-RAY DIFFRACTIONr_rigid_bond_restr3.56832716
LS refinement shellResolution: 1.8→1.847 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.266 54 -
Rwork0.144 1137 -
all-1191 -
obs--92.76 %

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