[English] 日本語
Yorodumi
- PDB-8tlr: Crystal Structure of human HRAS G12C covalently bound to AMG 510 -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 8tlr
TitleCrystal Structure of human HRAS G12C covalently bound to AMG 510
ComponentsGTPase HRas
KeywordsONCOPROTEIN / HRAS / H-Ras / sotorasib / Ras
Function / homology
Function and homology information


phospholipase C activator activity / GTPase complex / oncogene-induced cell senescence / positive regulation of miRNA metabolic process / positive regulation of ruffle assembly / T-helper 1 type immune response / positive regulation of wound healing / defense response to protozoan / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / Signaling by RAS GAP mutants ...phospholipase C activator activity / GTPase complex / oncogene-induced cell senescence / positive regulation of miRNA metabolic process / positive regulation of ruffle assembly / T-helper 1 type immune response / positive regulation of wound healing / defense response to protozoan / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / 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 / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / positive regulation of protein targeting to membrane / SHC1 events in ERBB4 signaling / Signalling to RAS / adipose tissue development / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Estrogen-stimulated signaling through PRKCZ / Schwann cell development / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / Signaling by FGFR4 in disease / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / protein-membrane adaptor activity / p38MAPK events / FRS-mediated FGFR1 signaling / Signaling by FGFR3 in disease / Tie2 Signaling / Signaling by FGFR2 in disease / EPHB-mediated forward signaling / myelination / 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 / Downstream signal transduction / intrinsic apoptotic signaling pathway / Ras activation upon Ca2+ influx through NMDA receptor / Insulin receptor signalling cascade / SHC1 events in ERBB2 signaling / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / animal organ morphogenesis / VEGFR2 mediated cell proliferation / positive regulation of epithelial cell proliferation / small monomeric GTPase / regulation of actin cytoskeleton organization / positive regulation of JNK cascade / FCERI mediated MAPK activation / RAF activation / Signaling by ERBB2 TMD/JMD mutants / cellular response to gamma radiation / Signaling by SCF-KIT / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII / regulation of long-term neuronal synaptic plasticity / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / positive regulation of type II interferon production / endocytosis / positive regulation of fibroblast proliferation / chemotaxis / 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 / cellular senescence / insulin receptor signaling pathway / DAP12 signaling / T cell receptor signaling pathway / MAPK cascade / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / regulation of cell population proliferation / G protein activity
Similarity search - Function
Small GTPase, Ras-type / Small GTPase Ras domain profile. / 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 nucleoside triphosphate hydrolase
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / AMG 510 (bound form) / GTPase HRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.70003947485 Å
AuthorsMorstein, J. / Guiley, K.Z. / Shokat, K.M.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)K99CA277358 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)5R01CA244550 United States
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Cell / Year: 2024
Title: Targeting Ras-, Rho-, and Rab-family GTPases via a conserved cryptic pocket.
Authors: Morstein, J. / Bowcut, V. / Fernando, M. / Yang, Y. / Zhu, L. / Jenkins, M.L. / Evans, J.T. / Guiley, K.Z. / Peacock, D.M. / Krahnke, S. / Lin, Z. / Taran, K.A. / Huang, B.J. / Stephen, A.G. ...Authors: Morstein, J. / Bowcut, V. / Fernando, M. / Yang, Y. / Zhu, L. / Jenkins, M.L. / Evans, J.T. / Guiley, K.Z. / Peacock, D.M. / Krahnke, S. / Lin, Z. / Taran, K.A. / Huang, B.J. / Stephen, A.G. / Burke, J.E. / Lightstone, F.C. / Shokat, K.M.
History
DepositionJul 27, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 31, 2024Provider: repository / Type: Initial release
Revision 1.1Sep 25, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification
Revision 1.3Nov 13, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.4Nov 20, 2024Group: Database references / Category: citation / Item: _citation.page_last

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: GTPase HRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,9514
Polymers18,9211
Non-polymers1,0303
Water1,928107
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)92.449, 92.449, 119.711
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number155
Space group name H-MH32
Space group name HallR32"
Symmetry operation#1: x,y,z
#2: -y,x-y,z
#3: -x+y,-x,z
#4: x-y,-y,-z
#5: -x,-x+y,-z
#6: y,x,-z
#7: x+1/3,y+2/3,z+2/3
#8: -y+1/3,x-y+2/3,z+2/3
#9: -x+y+1/3,-x+2/3,z+2/3
#10: x-y+1/3,-y+2/3,-z+2/3
#11: -x+1/3,-x+y+2/3,-z+2/3
#12: y+1/3,x+2/3,-z+2/3
#13: x+2/3,y+1/3,z+1/3
#14: -y+2/3,x-y+1/3,z+1/3
#15: -x+y+2/3,-x+1/3,z+1/3
#16: x-y+2/3,-y+1/3,-z+1/3
#17: -x+2/3,-x+y+1/3,-z+1/3
#18: y+2/3,x+1/3,-z+1/3
Components on special symmetry positions
IDModelComponents
11A-378-

HOH

21A-392-

HOH

31A-400-

HOH

41A-401-

HOH

51A-404-

HOH

-
Components

#1: Protein GTPase HRas


Mass: 18921.283 Da / Num. of mol.: 1 / Mutation: G12C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HRAS / Production host: Escherichia coli (E. coli) / References: UniProt: P01112
#2: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: GDP, energy-carrying molecule*YM
#3: Chemical ChemComp-MOV / AMG 510 (bound form) / 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-[(2S)-2-methyl-4-propanoylpiperazin-1-yl]-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]pyrido[2,3-d]pyrimidin-2(1H)-one


Mass: 562.610 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H32F2N6O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 107 / 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: 2.73 Å3/Da / Density % sol: 54.96 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 0.1 M MES 30% PEG 4000

-
Data collection

DiffractionMean temperature: 77.36 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 6, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.7→66.55 Å / Num. obs: 21565 / % possible obs: 99 % / Redundancy: 4.8 % / Biso Wilson estimate: 14.0826040808 Å2 / CC1/2: 0.976 / Net I/σ(I): 15.6
Reflection shellResolution: 1.7→1.73 Å / Mean I/σ(I) obs: 6.7 / Num. unique obs: 1132 / CC1/2: 0.569

-
Processing

Software
NameVersionClassification
Blu-Icedata collection
iMOSFLMdata reduction
Aimlessdata scaling
PHENIX1.10-1-2155phasing
PHENIX1.10-1-2155refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.70003947485→37.9650765581 Å / SU ML: 0.138899068314 / Cross valid method: FREE R-VALUE / σ(F): 1.38541061756 / Phase error: 19.6749289443
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.209801834667 1085 5.0336348875 %
Rwork0.183769867531 20470 -
obs0.185069278418 21555 98.5551643729 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 18.66422804 Å2
Refinement stepCycle: LAST / Resolution: 1.70003947485→37.9650765581 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1290 0 42 107 1439
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.007515454513421355
X-RAY DIFFRACTIONf_angle_d1.273060144031842
X-RAY DIFFRACTIONf_chiral_restr0.0605439186984202
X-RAY DIFFRACTIONf_plane_restr0.00454185563362231
X-RAY DIFFRACTIONf_dihedral_angle_d20.4251649513799
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.70004-1.77740.220704760551710.1890832947542525X-RAY DIFFRACTION99.8518518519
1.7774-1.87110.2395535143351550.1834894134342528X-RAY DIFFRACTION99.4809047089
1.8711-1.98830.179377393216850.1792725879142593X-RAY DIFFRACTION99.0018484288
1.9883-2.14190.196216756199980.1816329492132597X-RAY DIFFRACTION99.3731563422
2.1419-2.35740.2237487888661450.182786663352533X-RAY DIFFRACTION98.3474109438
2.3574-2.69840.2250357958971840.195102306512526X-RAY DIFFRACTION99.1584339554
2.6984-3.39940.2090185506111080.1943550947282573X-RAY DIFFRACTION97.5618631732

+
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