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Basic information

Entry
Database: PDB / ID: 6usx
TitleIdentification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer
ComponentsGTPase KRas
KeywordsHYDROLASE/INHIBITOR / Hydrolase inhibitor / 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
GUANOSINE-5'-DIPHOSPHATE / Chem-M1R / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.27 Å
AuthorsVigers, G.P. / Smith, D.J.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Identification of the Clinical Development CandidateMRTX849, a Covalent KRASG12CInhibitor for the Treatment of Cancer.
Authors: Fell, J.B. / Fischer, J.P. / Baer, B.R. / Blake, J.F. / Bouhana, K. / Briere, D.M. / Brown, K.D. / Burgess, L.E. / Burns, A.C. / Burkard, M.R. / Chiang, H. / Chicarelli, M.J. / Cook, A.W. / ...Authors: Fell, J.B. / Fischer, J.P. / Baer, B.R. / Blake, J.F. / Bouhana, K. / Briere, D.M. / Brown, K.D. / Burgess, L.E. / Burns, A.C. / Burkard, M.R. / Chiang, H. / Chicarelli, M.J. / Cook, A.W. / Gaudino, J.J. / Hallin, J. / Hanson, L. / Hartley, D.P. / Hicken, E.J. / Hingorani, G.P. / Hinklin, R.J. / Mejia, M.J. / Olson, P. / Otten, J.N. / Rhodes, S.P. / Rodriguez, M.E. / Savechenkov, P. / Smith, D.J. / Sudhakar, N. / Sullivan, F.X. / Tang, T.P. / Vigers, G.P. / Wollenberg, L. / Christensen, J.G. / Marx, M.A.
History
DepositionOct 28, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 22, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 22, 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 1.2Oct 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.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

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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)40,6708
Polymers38,7062
Non-polymers1,9646
Water1,35175
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,3354
Polymers19,3531
Non-polymers9823
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,3354
Polymers19,3531
Non-polymers9823
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)88.570, 156.490, 62.980
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number21
Space group name H-MC222

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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 / 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 / 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
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-M1R / 1-{4-[2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-7-(naphthalen-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]piperazin-1-yl}propan-1-one


Mass: 514.662 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H38N6O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 75 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.82 Å3/Da / Density % sol: 56.37 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.4 / Details: 29% PEG8K 0.1M NaCitrate pH 5.4 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 PILATUS 2M / Detector: PIXEL / Date: Jan 30, 2019 / Details: Osmic confocal mirrors
RadiationMonochromator: Osmic confocal mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.27→30 Å / Num. obs: 32164 / % possible obs: 84.7 % / Redundancy: 3.65 % / Rpim(I) all: 0.135 / Rrim(I) all: 0.25 / Net I/σ(I): 9.72
Reflection shellResolution: 2.27→2.42 Å / Redundancy: 3.3 % / Mean I/σ(I) obs: 4.7 / Num. unique obs: 2587 / Rpim(I) all: 0.135 / Rrim(I) all: 0.25 / % possible all: 69

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Processing

Software
NameVersionClassification
REFMAC5.8.0253refinement
iMOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4l8g.pdb

4l8g


Resolution: 2.27→29.51 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.902 / SU B: 6.423 / SU ML: 0.159 / Cross valid method: THROUGHOUT / ESU R: 0.329 / ESU R Free: 0.249
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflectionSelection details
Rfree0.2498 980 5.432 %Random
Rwork0.1873 ---
all0.191 ---
obs-18040 87.31 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 46.102 Å2
Baniso -1Baniso -2Baniso -3
1--3.266 Å2-0 Å20 Å2
2---0.484 Å2-0 Å2
3---3.75 Å2
Refinement stepCycle: LAST / Resolution: 2.27→29.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2685 0 134 75 2894
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0132875
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172555
X-RAY DIFFRACTIONr_angle_refined_deg1.9451.7253895
X-RAY DIFFRACTIONr_angle_other_deg1.341.5975928
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8825334
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.57922.611157
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.04815500
X-RAY DIFFRACTIONr_dihedral_angle_other_3_deg5.658152
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.0321520
X-RAY DIFFRACTIONr_chiral_restr0.0850.2369
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.023154
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02578
X-RAY DIFFRACTIONr_nbd_refined0.2040.2520
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1790.22395
X-RAY DIFFRACTIONr_nbtor_refined0.1750.21348
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0750.21376
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1590.2108
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0820.21
X-RAY DIFFRACTIONr_metal_ion_refined0.0770.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1660.210
X-RAY DIFFRACTIONr_nbd_other0.2110.238
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1580.23
X-RAY DIFFRACTIONr_mcbond_it4.5574.7131342
X-RAY DIFFRACTIONr_mcbond_other4.5584.7111341
X-RAY DIFFRACTIONr_mcangle_it5.5927.041674
X-RAY DIFFRACTIONr_mcangle_other5.5917.0431675
X-RAY DIFFRACTIONr_scbond_it5.4115.1341533
X-RAY DIFFRACTIONr_scbond_other5.455.2061439
X-RAY DIFFRACTIONr_scangle_it7.497.4982221
X-RAY DIFFRACTIONr_scangle_other7.6247.5912087
X-RAY DIFFRACTIONr_lrange_it8.79853.1253141
X-RAY DIFFRACTIONr_lrange_other8.92953.7052995
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.27-2.3290.299600.2048900.20914800.8470.89964.18920.182
2.329-2.3920.289650.20710550.21214530.8790.90977.08190.186
2.392-2.4610.324730.212460.20714300.8860.9292.23780.174
2.461-2.5360.357620.18912410.19713730.8860.92594.90170.165
2.536-2.6190.27390.1912320.19213490.8980.92594.21790.165
2.619-2.710.296770.19511030.20212890.9070.92391.54380.173
2.71-2.8110.287580.211080.20412710.8990.92391.73880.181
2.811-2.9250.269660.210230.20411890.9090.92991.58960.177
2.925-3.0540.286550.2089740.21211620.8940.92788.55420.193
3.054-3.2010.229460.1959250.19711220.910.93386.54190.189
3.201-3.3720.244410.1958700.19810590.930.93786.02460.194
3.372-3.5730.237690.1828430.18610050.9180.94990.74630.186
3.573-3.8160.236480.1828240.1859500.9450.95291.78950.186
3.816-4.1160.265530.1677720.1738970.9330.95591.97320.179
4.116-4.50.184630.1626960.1648400.9560.96390.35710.181
4.5-5.0170.22390.1646460.1677500.9490.96591.33330.182
5.017-5.7650.199220.1875370.1886710.9520.95683.30850.207
5.765-6.9950.216170.1824520.1835830.9380.95580.4460.198
6.995-9.6250.207200.1513320.1544620.9580.97376.19050.166
9.625-29.510.18370.2442900.2423120.980.95195.19230.261

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