[English] 日本語
Yorodumi
- PDB-6b0y: Crystal Structure of small molecule ARS-917 covalently bound to K... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 6b0y
TitleCrystal Structure of small molecule ARS-917 covalently bound to K-Ras G12C
ComponentsGTPase KRas
KeywordsSIGNALING PROTEIN / small GTPase domain / covalent inhibitor bound / switch II pocket / GDP bound
Function / homology
Function and homology information


forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / type I pneumocyte differentiation / 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 / regulation of synaptic transmission, GABAergic / type I pneumocyte differentiation / 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 / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / glial cell proliferation / SHC-mediated cascade:FGFR2 / 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 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / Erythropoietin activates RAS / Signaling by CSF3 (G-CSF) / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR2 signaling / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / positive regulation of glial cell proliferation / Signaling by FGFR2 in disease / FRS-mediated FGFR4 signaling / p38MAPK events / Signaling by FGFR3 in disease / homeostasis of number of cells within a tissue / Tie2 Signaling / FRS-mediated FGFR1 signaling / striated muscle cell differentiation / GRB2 events in EGFR signaling / FLT3 Signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / Signaling by FGFR1 in disease / GRB2 events in ERBB2 signaling / CD209 (DC-SIGN) signaling / Ras activation upon Ca2+ influx through NMDA receptor / NCAM signaling for neurite out-growth / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / small monomeric GTPase / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / RAF activation / Constitutive Signaling by EGFRvIII / regulation of long-term neuronal synaptic plasticity / Signaling by high-kinase activity BRAF mutants / Signaling by ERBB2 ECD mutants / MAP2K and MAPK activation / visual learning / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / G protein activity / cytoplasmic side of plasma membrane / Signaling by CSF1 (M-CSF) in myeloid cells / Regulation of RAS by GAPs / RAS processing / Negative regulation of MAPK 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 / MAPK cascade / DAP12 signaling / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Ca2+ pathway / gene expression / actin cytoskeleton organization / RAF/MAP kinase cascade / neuron apoptotic process / negative regulation of neuron apoptotic process / mitochondrial outer membrane / 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 / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-8ZG / GUANOSINE-5'-DIPHOSPHATE / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.43 Å
AuthorsHansen, R. / Peters, U. / Babbar, A. / Chen, Y. / Feng, J. / Janes, M.R. / Li, L.-S. / Ren, P. / Liu, Y. / Zarrinkar, P.P.
CitationJournal: Nat. Struct. Mol. Biol. / Year: 2018
Title: The reactivity-driven biochemical mechanism of covalent KRASG12Cinhibitors.
Authors: Hansen, R. / Peters, U. / Babbar, A. / Chen, Y. / Feng, J. / Janes, M.R. / Li, L.S. / Ren, P. / Liu, Y. / Zarrinkar, P.P.
History
DepositionSep 15, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 16, 2018Provider: repository / Type: Initial release
Revision 1.1May 30, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.pdbx_database_id_PubMed ..._citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Nov 7, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 4, 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_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_alt_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr2_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_alt_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _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.pdbx_ptnr1_label_alt_id / _struct_conn.pdbx_ptnr2_label_alt_id / _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 / _struct_conn.ptnr2_symmetry
Revision 1.4Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: GTPase KRas
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,82613
Polymers38,7062
Non-polymers2,12111
Water5,927329
1
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,3676
Polymers19,3531
Non-polymers1,0145
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4597
Polymers19,3531
Non-polymers1,1066
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)33.430, 39.660, 61.850
Angle α, β, γ (deg.)77.450, 81.710, 77.120
Int Tables number1
Space group name H-MP1

-
Components

-
Protein , 1 types, 2 molecules AB

#1: Protein GTPase KRas / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras


Mass: 19352.785 Da / Num. of mol.: 2 / Fragment: UNP residues 1-169 / Mutation: G12C, C51S, C80L, C118S
Source method: isolated from a genetically manipulated source
Details: GTPase domain / Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Plasmid: pJExpress411 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P01116

-
Non-polymers , 5 types, 340 molecules

#2: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
#3: Chemical ChemComp-8ZG / 1-{4-[6-chloro-7-(2-fluorophenyl)quinazolin-4-yl]piperazin-1-yl}propan-1-one


Mass: 398.861 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H20ClFN4O
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 329 / Source method: isolated from a natural source / Formula: H2O

-
Details

Has protein modificationY

-
Experimental details

-
Experiment

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

-
Sample preparation

CrystalDensity Matthews: 2.01 Å3/Da / Density % sol: 38.68 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 27% PEG 4000, 0.2 M CaCl2, 0.1 M Tris pH=8.5

-
Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 10, 2014
RadiationMonochromator: Double-crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.43→37.943 Å / Num. obs: 51554 / % possible obs: 92.7 % / Redundancy: 1.6 % / Rpim(I) all: 0.076 / Rrim(I) all: 0.108 / Rsym value: 0.076 / Net I/av σ(I): 5 / Net I/σ(I): 5.5
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) allRsym value% possible all
1.43-1.511.60.281273050.2810.3970.28189.9
1.51-1.61.60.2022.969490.2010.2850.20290
1.6-1.711.60.1554.166120.1550.2190.15592.1
1.71-1.851.60.1265.162080.1260.1780.12692.1
1.85-2.021.60.0985.557040.0980.1380.09892.9
2.02-2.261.70.0836.852610.0830.1180.08393.6
2.26-2.611.60.0737.147020.0730.1030.07395.4
2.61-3.21.70.0637.639960.0630.090.06396.2
3.2-4.521.60.0578.831060.0570.080.05796.6
4.52-37.9431.70.0539.617110.0530.0750.05396.6

-
Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation4.51 Å37.94 Å
Translation4.51 Å37.94 Å

-
Processing

Software
NameVersionClassification
iMOSFLMdata collection
SCALA3.3.21data scaling
PHASER2.5.6phasing
REFMAC5.8.0073refinement
PDB_EXTRACT3.22data extraction
iMOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5F2E

5f2e


Resolution: 1.43→37.943 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.942 / SU B: 2.831 / SU ML: 0.055 / SU R Cruickshank DPI: 0.0775 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.078 / ESU R Free: 0.079
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2074 2501 4.9 %RANDOM
Rwork0.1739 ---
obs0.1755 49052 92.72 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 45.31 Å2 / Biso mean: 13.549 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1--0.21 Å2-0.24 Å20.05 Å2
2--0.37 Å20.72 Å2
3----0.03 Å2
Refinement stepCycle: final / Resolution: 1.43→37.943 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2642 0 134 350 3126
Biso mean--12.08 22.44 -
Num. residues----335
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0210.0192946
X-RAY DIFFRACTIONr_bond_other_d0.0010.022750
X-RAY DIFFRACTIONr_angle_refined_deg2.2072.0114010
X-RAY DIFFRACTIONr_angle_other_deg2.1753.0016334
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9995363
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.07924.191136
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.68215507
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.3411521
X-RAY DIFFRACTIONr_chiral_restr0.1350.2444
X-RAY DIFFRACTIONr_gen_planes_refined0.0140.023327
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02670
LS refinement shellResolution: 1.43→1.467 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.25 179 -
Rwork0.235 3531 -
all-3710 -
obs--89.38 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.61980.08480.18640.2126-0.05460.4766-0.03820.05290.00280.01530.0136-0.00830.00030.00370.02460.01010.00490.00130.0270.00080.0019-18.3999.0867.136
20.22250.0396-0.08090.3494-0.13740.4169-0.0256-0.01970.0034-0.0001-0.004-0.00890.0156-0.00990.02960.00320.00180.00010.04440.00930.0054-2.343-3.07135.467
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 168
2X-RAY DIFFRACTION1A200 - 220
3X-RAY DIFFRACTION2B2 - 168
4X-RAY DIFFRACTION2B200 - 220

+
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