[English] 日本語
Yorodumi
- PDB-6ut0: Identification of the Clinical Development Candidate MRTX849, a C... -

+
Open data


ID or keywords:

Loading...

-
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 / 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 / skeletal muscle cell differentiation / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants ...forebrain astrocyte development / negative regulation of epithelial cell differentiation / 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 / skeletal muscle cell differentiation / 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 / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / glial cell proliferation / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by CSF3 (G-CSF) / Signaling by FGFR4 in disease / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / membrane-membrane adaptor activity / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / Tie2 Signaling / positive regulation of glial cell proliferation / FRS-mediated FGFR1 signaling / homeostasis of number of cells within a tissue / Signaling by FGFR2 in disease / striated muscle cell differentiation / 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 / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Ras activation upon Ca2+ influx through NMDA receptor / Downstream signal transduction / SHC1 events in ERBB2 signaling / Insulin receptor signalling cascade / 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 / RAF activation / regulation of long-term neuronal synaptic plasticity / Signaling by ERBB2 TMD/JMD mutants / Signaling by high-kinase activity BRAF mutants / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / visual learning / Signaling by ERBB2 KD Mutants / cytoplasmic side of plasma membrane / Regulation of RAS by GAPs / RAS processing / Signaling by CSF1 (M-CSF) in myeloid cells / Signaling by RAF1 mutants / Negative regulation of MAPK pathway / 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 / MAPK cascade / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / G protein activity / actin cytoskeleton organization / Ca2+ pathway / RAF/MAP kinase cascade / neuron apoptotic process / gene expression / negative regulation of neuron apoptotic process / mitochondrial outer membrane / Ras protein signal transduction / Golgi membrane / focal adhesion / GTPase activity
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 / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 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
Revision 1.3Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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

-
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


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


Mass: 18.015 Da / Num. of mol.: 446 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
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

-
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

-
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

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more