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- PDB-4us2: The crystal structure of H-Ras and SOS in complex with ligands -

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Basic information

Entry
Database: PDB / ID: 4us2
TitleThe crystal structure of H-Ras and SOS in complex with ligands
Components
  • GTPASE HRAS
  • SON OF SEVENLESS HOMOLOG 1
KeywordsSIGNALING PROTEIN
Function / homology
Function and homology information


midbrain morphogenesis / regulation of pro-B cell differentiation / vitellogenesis / pericardium morphogenesis / cardiac atrium morphogenesis / heart trabecula morphogenesis / phospholipase C activator activity / regulation of T cell differentiation in thymus / GTPase complex / Interleukin-15 signaling ...midbrain morphogenesis / regulation of pro-B cell differentiation / vitellogenesis / pericardium morphogenesis / cardiac atrium morphogenesis / heart trabecula morphogenesis / phospholipase C activator activity / regulation of T cell differentiation in thymus / GTPase complex / Interleukin-15 signaling / positive regulation of small GTPase mediated signal transduction / Activation of RAC1 / oncogene-induced cell senescence / positive regulation of ruffle assembly / blood vessel morphogenesis / Signaling by LTK / negative regulation of GTPase activity / positive regulation of miRNA metabolic process / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / positive regulation of epidermal growth factor receptor signaling pathway / T-helper 1 type immune response / epidermal growth factor receptor binding / Regulation of KIT signaling / NRAGE signals death through JNK / leukocyte migration / positive regulation of wound healing / regulation of T cell proliferation / roof of mouth development / eyelid development in camera-type eye / defense response to protozoan / B cell homeostasis / Fc-epsilon receptor signaling pathway / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / GRB2:SOS provides linkage to MAPK signaling for Integrins / neurotrophin TRK receptor signaling pathway / RAS signaling downstream of NF1 loss-of-function variants / RET signaling / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / hair follicle development / positive regulation of protein targeting to membrane / fibroblast growth factor receptor signaling pathway / Signalling to RAS / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / Role of LAT2/NTAL/LAB on calcium mobilization / Interleukin receptor SHC signaling / Signal attenuation / adipose tissue development / 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 / Schwann cell development / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR2 signaling / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / Signaling by FGFR2 in disease / FRS-mediated FGFR4 signaling / p38MAPK events / Signaling by FGFR3 in disease / Tie2 Signaling / FRS-mediated FGFR1 signaling / GRB2 events in EGFR signaling / FLT3 Signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / EPHB-mediated forward signaling / RAC1 GTPase cycle / Signaling by FGFR1 in disease / myelination / GRB2 events in ERBB2 signaling / intrinsic apoptotic signaling pathway / 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 / GTPase activator activity / FCERI mediated Ca+2 mobilization / positive regulation of epithelial cell proliferation / insulin-like growth factor receptor signaling pathway / positive regulation of GTPase activity / T cell activation / 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-like guanine nucleotide exchange factor ...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-like guanine nucleotide exchange factor / Ras guanine-nucleotide exchange factors N-terminal domain profile. / Ras guanine nucleotide exchange factor domain superfamily / Ras guanine-nucleotide exchange factor, catalytic 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 / SOS1/NGEF-like PH 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 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 / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / Orthogonal Bundle / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-L7S / GTPase HRas / Son of sevenless homolog 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.48 Å
AuthorsWinter, J.J.G. / Anderson, M. / Blades, K. / Brassington, C. / Breeze, A.L. / Chresta, C. / Embrey, K. / Fairley, G. / Faulder, P. / Finlay, M.R.V. ...Winter, J.J.G. / Anderson, M. / Blades, K. / Brassington, C. / Breeze, A.L. / Chresta, C. / Embrey, K. / Fairley, G. / Faulder, P. / Finlay, M.R.V. / Kettle, J.G. / Nowak, T. / Overman, R. / Patel, S.J. / Perkins, P. / Spadola, L. / Tart, J. / Tucker, J. / Wrigley, G.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Small Molecule Binding Sites on the Ras:SOS Complex Can be Exploited for Inhibition of Ras Activation.
Authors: Winter, J. / Anderson, M. / Blades, K. / Chresta, C. / Embrey, K.J. / Fairley, G. / Faulder, P. / Finlay, M.R.V. / Kettle, J.G. / Nowak, T. / Overman, R. / Patel, S.J. / Perkins, P. / ...Authors: Winter, J. / Anderson, M. / Blades, K. / Chresta, C. / Embrey, K.J. / Fairley, G. / Faulder, P. / Finlay, M.R.V. / Kettle, J.G. / Nowak, T. / Overman, R. / Patel, S.J. / Perkins, P. / Spadola, L. / Tart, J. / Tucker, J.A. / Wrigley, G.
History
DepositionJul 2, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 4, 2015Provider: repository / Type: Initial release
Revision 1.1Mar 25, 2015Group: Database references
Revision 1.2Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Oct 9, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
R: GTPASE HRAS
S: SON OF SEVENLESS HOMOLOG 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)78,5073
Polymers78,2612
Non-polymers2461
Water5,405300
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3290 Å2
ΔGint-7 kcal/mol
Surface area28970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)149.710, 149.710, 200.080
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number97
Space group name H-MI422

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Components

#1: Protein GTPASE HRAS / H-RAS / H-RAS-1 / HA-RAS / TRANSFORMING PROTEIN P21 / C-H-RAS / P21RAS / GTPASE HRAS / N-TERMINALLY PROCESSED


Mass: 21083.557 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 1-166
Source method: isolated from a genetically manipulated source
Details: COVALENT LINK TO COMPOUND VIA CYS 118 / Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P01112
#2: Protein SON OF SEVENLESS HOMOLOG 1 / SON OF SEVENLESS-1 / SOS-1


Mass: 57177.426 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 564-1049
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: Q07889
#3: Chemical ChemComp-L7S / 3-[(3R)-1-ethyl-2,5-dioxopyrrolidin-3-yl]benzamide


Mass: 246.262 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H14N2O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 300 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
Nonpolymer details3-(1-ETHYL-2,5-DIOXO-2,5-DIHYDRO-1H-PYRROL-3-YL)BENZAMIDE COVALENTLY BOUND TO R CYS118 TO FORM L7S

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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: 3.58 Å3/Da / Density % sol: 65.65 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.976
DetectorType: ADSC CCD / Detector: CCD / Date: Dec 15, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.48→52.93 Å / Num. obs: 39233 / % possible obs: 97.3 % / Observed criterion σ(I): 0 / Redundancy: 6.9 % / Biso Wilson estimate: 57.15 Å2 / Rmerge(I) obs: 0.12 / Net I/σ(I): 11.6
Reflection shellResolution: 2.48→2.57 Å / Redundancy: 6.8 % / Rmerge(I) obs: 0.76 / Mean I/σ(I) obs: 2.5 / % possible all: 99

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1BKD

1bkd


Resolution: 2.48→52.93 Å / Cor.coef. Fo:Fc: 0.9374 / Cor.coef. Fo:Fc free: 0.9071 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.263 / SU Rfree Blow DPI: 0.209
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2278 1963 5 %RANDOM
Rwork0.1896 ---
obs0.1915 39224 96.81 %-
Displacement parametersBiso mean: 49.57 Å2
Baniso -1Baniso -2Baniso -3
1--0.0449 Å20 Å20 Å2
2---0.0449 Å20 Å2
3---0.0898 Å2
Refine analyzeLuzzati coordinate error obs: 0.291 Å
Refinement stepCycle: LAST / Resolution: 2.48→52.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5052 0 18 300 5370
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0110186HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0118418HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2262SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes143HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1469HARMONIC5
X-RAY DIFFRACTIONt_it10186HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.2
X-RAY DIFFRACTIONt_other_torsion16.63
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion676SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact11211SEMIHARMONIC4
LS refinement shellResolution: 2.48→2.54 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2746 137 4.67 %
Rwork0.2285 2798 -
all0.2307 2935 -
obs--96.81 %

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