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- PDB-6d5v: Ras:SOS:Ras in complex with a small molecule activator -

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Basic information

Entry
Database: PDB / ID: 6d5v
TitleRas:SOS:Ras in complex with a small molecule activator
Components
  • (GTPase HRasHRAS) x 2
  • Son of sevenless homolog 1
KeywordsSIGNALING PROTEIN / Ras / SOS / inhibitor / ONCOPROTEIN / Protein-protein complex / MAPK
Function / homology
Function and homology information


midbrain morphogenesis / regulation of pro-B cell differentiation / vitellogenesis / pericardium morphogenesis / cardiac atrium morphogenesis / heart trabecula morphogenesis / regulation of T cell differentiation in thymus / GTPase complex / positive regulation of small GTPase mediated signal transduction / Interleukin-15 signaling ...midbrain morphogenesis / regulation of pro-B cell differentiation / vitellogenesis / pericardium morphogenesis / cardiac atrium morphogenesis / heart trabecula morphogenesis / regulation of T cell differentiation in thymus / GTPase complex / positive regulation of small GTPase mediated signal transduction / Interleukin-15 signaling / Activation of RAC1 / oncogene-induced cell senescence / positive regulation of ruffle assembly / blood vessel morphogenesis / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / negative regulation of GTPase activity / positive regulation of miRNA metabolic process / positive regulation of epidermal growth factor receptor signaling pathway / T-helper 1 type immune response / epidermal growth factor receptor binding / Regulation of KIT signaling / positive regulation of wound healing / leukocyte migration / NRAGE signals death through JNK / regulation of T cell proliferation / roof of mouth development / defense response to protozoan / eyelid development in camera-type eye / Fc-epsilon receptor signaling pathway / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / neurotrophin TRK receptor signaling pathway / GRB2:SOS provides linkage to MAPK signaling for Integrins / B cell homeostasis / RAS signaling downstream of NF1 loss-of-function variants / positive regulation of protein targeting to membrane / SOS-mediated signalling / Activated NTRK3 signals through RAS / RET signaling / Activated NTRK2 signals through RAS / hair follicle development / SHC1 events in ERBB4 signaling / Signalling to RAS / fibroblast growth factor receptor signaling pathway / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Role of LAT2/NTAL/LAB on calcium mobilization / adipose tissue development / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / Interleukin receptor SHC signaling / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / positive regulation of phospholipase C activity / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Schwann cell development / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / protein-membrane adaptor activity / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / FRS-mediated FGFR1 signaling / Tie2 Signaling / Signaling by FGFR2 in disease / RAC1 GTPase cycle / GRB2 events in EGFR signaling / EPHB-mediated forward signaling / SHC1 events in EGFR signaling / myelination / molecular condensate scaffold activity / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / Ras activation upon Ca2+ influx through NMDA receptor / FLT3 Signaling / Signaling by FGFR1 in disease / GRB2 events in ERBB2 signaling / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / GTPase activator activity / SHC1 events in ERBB2 signaling / Downstream signal transduction / Insulin receptor signalling cascade / Constitutive Signaling by Overexpressed ERBB2 / FCERI mediated Ca+2 mobilization / guanyl-nucleotide exchange factor activity / intrinsic apoptotic signaling pathway / small monomeric GTPase / G protein activity / insulin-like growth factor receptor signaling pathway / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants
Similarity search - Function
Son of sevenless (SoS) protein; Chain S, domain 1 / Son of sevenless (SoS) protein Chain: S domain 1 / Son of Sevenless (SoS) protein; Chain S, domain 2 / Ras guanine-nucleotide exchange factors catalytic domain / Ras guanine-nucleotide exchange factor, conserved site / Ras Guanine-nucleotide exchange factors domain signature. / RasGEF N-terminal motif / Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal motif / Ras-like guanine nucleotide exchange factor, N-terminal / Ras guanine-nucleotide exchange factors N-terminal domain profile. ...Son of sevenless (SoS) protein; Chain S, domain 1 / Son of sevenless (SoS) protein Chain: S domain 1 / Son of Sevenless (SoS) protein; Chain S, domain 2 / Ras guanine-nucleotide exchange factors catalytic domain / Ras guanine-nucleotide exchange factor, conserved site / Ras Guanine-nucleotide exchange factors domain signature. / RasGEF N-terminal motif / Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal motif / Ras-like guanine nucleotide exchange factor, N-terminal / Ras guanine-nucleotide exchange factors N-terminal domain profile. / Ras-like guanine nucleotide exchange factor / Ras guanine-nucleotide exchange factor, catalytic domain superfamily / Ras guanine nucleotide exchange factor domain superfamily / RasGEF domain / Ras guanine-nucleotide exchange factors catalytic domain profile. / Guanine nucleotide exchange factor for Ras-like small GTPases / Ras guanine-nucleotide exchange factors catalytic domain / Dbl homology (DH) domain superfamily / RhoGEF domain / Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases / Dbl homology (DH) domain / Dbl homology (DH) domain profile. / Small GTPase, Ras-type / small GTPase Ras family profile. / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Histone-fold / Small GTP-binding protein domain / PH-like domain superfamily / P-loop containing nucleotide triphosphate hydrolases / Up-down Bundle / P-loop containing nucleoside triphosphate hydrolase / Rossmann fold / Orthogonal Bundle / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-FVY / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GTPase HRas / Son of sevenless homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.04 Å
AuthorsPhan, J. / Hodges, T. / Fesik, S.W.
Funding support United States, 1items
OrganizationGrant numberCountry
Lustgarten United States
Citation
Journal: J. Med. Chem. / Year: 2018
Title: Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS.
Authors: Hodges, T.R. / Abbott, J.R. / Little, A.J. / Sarkar, D. / Salovich, J.M. / Howes, J.E. / Akan, D.T. / Sai, J. / Arnold, A.L. / Browning, C. / Burns, M.C. / Sobolik, T. / Sun, Q. / Beesetty, ...Authors: Hodges, T.R. / Abbott, J.R. / Little, A.J. / Sarkar, D. / Salovich, J.M. / Howes, J.E. / Akan, D.T. / Sai, J. / Arnold, A.L. / Browning, C. / Burns, M.C. / Sobolik, T. / Sun, Q. / Beesetty, Y. / Coker, J.A. / Scharn, D. / Stadtmueller, H. / Rossanese, O.W. / Phan, J. / Waterson, A.G. / McConnell, D.B. / Fesik, S.W.
#1: Journal: Proc. Natl. Acad. Sci. U.S.A. / Year: 2014
Title: Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange.
Authors: Burns, M.C. / Sun, Q. / Daniels, R.N. / Camper, D. / Kennedy, J.P. / Phan, J. / Olejniczak, E.T. / Lee, T. / Waterson, A.G. / Rossanese, O.W. / Fesik, S.W.
History
DepositionApr 19, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 19, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 7, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 1.2Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
Q: GTPase HRas
R: GTPase HRas
S: Son of sevenless homolog 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)95,2126
Polymers94,3623
Non-polymers8503
Water16,466914
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7060 Å2
ΔGint-32 kcal/mol
Surface area35530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)182.822, 182.822, 177.866
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number97
Space group name H-MI422
Components on special symmetry positions
IDModelComponents
11S-1627-

HOH

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Components

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Protein , 3 types, 3 molecules QRS

#1: Protein GTPase HRas / HRAS / H-Ras-1 / Ha-Ras / Transforming protein p21 / c-H-ras / p21ras


Mass: 18840.146 Da / Num. of mol.: 1 / Mutation: Y64A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HRAS, HRAS1 / Production host: Escherichia coli (E. coli) / References: UniProt: P01112
#2: Protein GTPase HRas / HRAS / H-Ras-1 / Ha-Ras / Transforming protein p21 / c-H-ras / p21ras


Mass: 18932.242 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HRAS, HRAS1 / Production host: Escherichia coli (E. coli) / References: UniProt: P01112
#3: Protein Son of sevenless homolog 1 / SOS-1


Mass: 56589.781 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SOS1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q07889

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Non-polymers , 4 types, 917 molecules

#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / 5'-Guanylyl imidodiphosphate


Mass: 522.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N6O13P3
Comment: GppNHp, GMPPNP, energy-carrying molecule analogue*YM
#6: Chemical ChemComp-FVY / 1-[(3-chloro-4-fluorophenyl)methyl]-5,6-dimethyl-1H-benzimidazol-2-amine


Mass: 303.762 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H15ClFN3
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 914 / Source method: isolated from a natural source / Formula: H2O

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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: 3.2 Å3/Da / Density % sol: 60 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.1 M sodium acetate, 2.0 M sodium formate, pH 4.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.98 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Mar 21, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.04→50 Å / Num. obs: 95040 / % possible obs: 100 % / Redundancy: 18.3 % / Rpim(I) all: 0.029 / Net I/σ(I): 22.6
Reflection shellResolution: 2.05→2.08 Å / Num. unique obs: 4687 / Rpim(I) all: 0.204

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Processing

Software
NameVersionClassification
PHENIX1.8.4_1496refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4NYI

4nyi


Resolution: 2.04→35.854 Å / SU ML: 0.18 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 18.15
RfactorNum. reflection% reflection
Rfree0.1862 1998 2.1 %
Rwork0.1669 --
obs0.1673 94992 99.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.04→35.854 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6515 0 54 917 7486
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0086781
X-RAY DIFFRACTIONf_angle_d1.0629188
X-RAY DIFFRACTIONf_dihedral_angle_d14.0072618
X-RAY DIFFRACTIONf_chiral_restr0.0431006
X-RAY DIFFRACTIONf_plane_restr0.0041194
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0402-2.09120.21441400.1946550X-RAY DIFFRACTION100
2.0912-2.14770.21371420.18436560X-RAY DIFFRACTION100
2.1477-2.21090.20231400.17656593X-RAY DIFFRACTION100
2.2109-2.28220.21321480.17826548X-RAY DIFFRACTION100
2.2822-2.36380.21361360.18056601X-RAY DIFFRACTION100
2.3638-2.45840.25141390.17836611X-RAY DIFFRACTION100
2.4584-2.57030.20571410.17716601X-RAY DIFFRACTION100
2.5703-2.70570.20191460.18516599X-RAY DIFFRACTION100
2.7057-2.87520.22461400.18456636X-RAY DIFFRACTION100
2.8752-3.09710.22631450.17796639X-RAY DIFFRACTION100
3.0971-3.40850.18331420.16626665X-RAY DIFFRACTION100
3.4085-3.90120.1521450.14546686X-RAY DIFFRACTION100
3.9012-4.91320.13261460.13516750X-RAY DIFFRACTION100
4.9132-35.85990.18231480.17586955X-RAY DIFFRACTION100

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