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Basic information

Entry
Database: PDB / ID: 6ut0
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-M1X / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.94 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 29, 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
C: GTPase KRas
D: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,70616
Polymers77,4114
Non-polymers4,29512
Water8,035446
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4264
Polymers19,3531
Non-polymers1,0743
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4264
Polymers19,3531
Non-polymers1,0743
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4264
Polymers19,3531
Non-polymers1,0743
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4264
Polymers19,3531
Non-polymers1,0743
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)74.918, 61.800, 76.050
Angle α, β, γ (deg.)90.000, 111.370, 90.000
Int Tables number4
Space group name H-MP1211

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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.: 4 / 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 / MRTX849 / bound form / Guanosine diphosphate


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 4 / 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.: 4 / Source method: obtained synthetically / Formula: Mg
#4: Chemical
ChemComp-M1X / {(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-1-[(2S)-2-fluoropropanoyl]piperazin-2-yl}acetonitrile


Mass: 606.133 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C32H37ClFN7O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 446 / 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: 2.12 Å3/Da / Density % sol: 41.92 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 32% PEG 4K 0.1M NaOAc (unbuffered) 8% 2-Propanol

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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: Nov 29, 2017 / 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: 1.94→30 Å / Num. obs: 47734 / % possible obs: 96.3 % / Redundancy: 6.45 % / Rmerge(I) obs: 0.076 / Net I/σ(I): 15.8
Reflection shellResolution: 1.94→1.99 Å / Redundancy: 5.4 % / Rmerge(I) obs: 0.21 / Mean I/σ(I) obs: 5.7 / Num. unique obs: 3042 / Rpim(I) all: 0.102 / Rrim(I) all: 0.235 / % possible all: 92.8

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Processing

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

4l8g


Resolution: 1.94→28.321 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.921 / SU B: 4.071 / SU ML: 0.116 / Cross valid method: THROUGHOUT / ESU R: 0.197 / ESU R Free: 0.166
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.222 2375 5.121 %
Rwork0.1746 --
all0.177 --
obs-46376 96.318 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 20.445 Å2
Baniso -1Baniso -2Baniso -3
1--0.921 Å2-0 Å20.595 Å2
2---0.122 Å2-0 Å2
3---0.441 Å2
Refinement stepCycle: LAST / Resolution: 1.94→28.321 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5413 0 288 446 6147
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0135825
X-RAY DIFFRACTIONr_bond_other_d0.0010.0175164
X-RAY DIFFRACTIONr_angle_refined_deg1.7871.7317898
X-RAY DIFFRACTIONr_angle_other_deg1.361.59811989
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5585677
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.29922.681317
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.629151016
X-RAY DIFFRACTIONr_dihedral_angle_other_3_deg11.309154
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.51540
X-RAY DIFFRACTIONr_chiral_restr0.0720.2744
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.026401
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021163
X-RAY DIFFRACTIONr_nbd_refined0.2150.21257
X-RAY DIFFRACTIONr_symmetry_nbd_other0.180.25082
X-RAY DIFFRACTIONr_nbtor_refined0.1740.22865
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0770.22601
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1640.2411
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0010.21
X-RAY DIFFRACTIONr_metal_ion_refined0.0180.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2020.243
X-RAY DIFFRACTIONr_nbd_other0.2270.294
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1880.230
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.0030.21
X-RAY DIFFRACTIONr_mcbond_it1.6411.9982708
X-RAY DIFFRACTIONr_mcbond_other1.6391.9972707
X-RAY DIFFRACTIONr_mcangle_it2.4532.9873379
X-RAY DIFFRACTIONr_mcangle_other2.4532.9883380
X-RAY DIFFRACTIONr_scbond_it2.262.2863117
X-RAY DIFFRACTIONr_scbond_other2.2792.3152917
X-RAY DIFFRACTIONr_scangle_it3.5413.3254517
X-RAY DIFFRACTIONr_scangle_other3.5953.3624229
X-RAY DIFFRACTIONr_lrange_it5.18624.466884
X-RAY DIFFRACTIONr_lrange_other5.1224.5496474
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
1.94-1.990.2681840.231610.20435440.8820.89694.38490.166
1.99-2.0440.2431490.20130950.20334230.8970.90394.77070.17
2.044-2.1030.2411580.19530320.19833610.90.9194.91220.167
2.103-2.1680.2571240.18329300.18632190.9150.92194.87420.154
2.168-2.2380.2321380.17628440.17931540.9170.93194.54660.151
2.238-2.3160.2091650.17527390.17730440.930.93495.40080.15
2.316-2.4030.2751410.18726560.19229350.8910.92195.29810.158
2.403-2.5010.2741440.19325560.19728560.9070.92194.53780.166
2.501-2.6110.2531320.17924610.18327020.9110.93595.9660.158
2.611-2.7370.231710.17823910.18126060.9240.94298.31160.161
2.737-2.8840.2451180.17823430.18124960.9280.94198.59780.165
2.884-3.0570.2071200.17221930.17423440.9350.94898.67750.163
3.057-3.2650.221020.16720830.16922150.9360.95298.64560.166
3.265-3.5230.2341050.17419310.17620520.9310.95199.22030.177
3.523-3.8530.1861220.15617840.15819240.9590.96499.06450.162
3.853-4.2980.186950.14916040.15117170.9640.9798.95170.159
4.298-4.9440.169680.14714450.14815400.9650.97198.24670.159
4.944-6.0090.201700.18811880.18913190.9640.96195.37530.198
6.009-8.3130.215340.1699620.17110400.960.96595.76920.176
8.313-28.3210.155350.1756020.1746390.9860.97899.6870.185

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