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- PDB-4us0: The crystal structure of H-Ras and SOS in complex with ligands -

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Basic information

Entry
Database: PDB / ID: 4us0
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 / oncogene-induced cell senescence / Activation of RAC1 / blood vessel morphogenesis / positive regulation of miRNA metabolic process / Signaling by LTK / positive regulation of ruffle assembly / epidermal growth factor receptor binding / T-helper 1 type immune response / Regulation of KIT signaling / positive regulation of epidermal growth factor receptor signaling pathway / leukocyte migration / NRAGE signals death through JNK / positive regulation of wound healing / defense response to protozoan / neurotrophin TRK receptor signaling pathway / Fc-epsilon receptor signaling pathway / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / eyelid development in camera-type eye / GRB2:SOS provides linkage to MAPK signaling for Integrins / roof of mouth development / regulation of T cell proliferation / B cell homeostasis / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / RET signaling / RAS signaling downstream of NF1 loss-of-function variants / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / fibroblast growth factor receptor signaling pathway / positive regulation of protein targeting to membrane / Role of LAT2/NTAL/LAB on calcium mobilization / SHC1 events in ERBB4 signaling / hair follicle development / Interleukin receptor SHC signaling / Signalling to RAS / adipose tissue development / Signal attenuation / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Schwann cell development / Estrogen-stimulated signaling through PRKCZ / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / SHC-mediated cascade:FGFR2 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR4 / 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 / p38MAPK events / FRS-mediated FGFR1 signaling / Signaling by FGFR3 in disease / protein-membrane adaptor activity / Tie2 Signaling / Signaling by FGFR2 in disease / RAC1 GTPase cycle / myelination / GRB2 events in EGFR signaling / EPHB-mediated forward signaling / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / FCERI mediated Ca+2 mobilization / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Downstream signal transduction / intrinsic apoptotic signaling pathway / Insulin receptor signalling cascade / insulin-like growth factor receptor signaling pathway / SHC1 events in ERBB2 signaling / Ras activation upon Ca2+ influx through NMDA receptor / GTPase activator activity / axon guidance / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / guanyl-nucleotide exchange factor activity / T cell activation
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 domain 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
1-ETHYL-PYRROLIDINE-2,5-DIONE / GTPase HRas / Son of sevenless homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.17 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 1.2Sep 23, 2015Group: Data collection
Revision 1.3Jan 13, 2016Group: Data collection
Revision 2.0Mar 1, 2023Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations / Non-polymer description / Other / Source and taxonomy / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / database_2 / entity / entity_name_com / entity_src_gen / pdbx_database_status / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / struct_conn / struct_ref / struct_ref_seq_dif / struct_site
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.type_symbol / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_ec / _entity_name_com.name / _entity_src_gen.gene_src_common_name / _entity_src_gen.pdbx_beg_seq_num / _entity_src_gen.pdbx_end_seq_num / _entity_src_gen.pdbx_gene_src_gene / _entity_src_gen.pdbx_gene_src_scientific_name / _entity_src_gen.pdbx_seq_type / _pdbx_database_status.status_code_sf / _pdbx_entity_nonpoly.comp_id / _pdbx_entity_nonpoly.name / _pdbx_nonpoly_scheme.mon_id / _pdbx_nonpoly_scheme.pdb_mon_id / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_ref.pdbx_align_begin / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq_dif.details / _struct_site.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 2.1Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 2.2Nov 6, 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)78,3883
Polymers78,2612
Non-polymers1271
Water8,881493
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3550 Å2
ΔGint-3.8 kcal/mol
Surface area29130 Å2
MethodPISA
Unit cell
Length a, b, c (Å)149.217, 149.217, 201.038
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-1 / Ha-Ras / Transforming protein p21 / c-H-ras / p21ras


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) / Gene: HRAS, HRAS1 / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P01112, small monomeric GTPase
#2: Protein Son of sevenless homolog 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) / Gene: SOS1 / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: Q07889
#3: Chemical ChemComp-NEN / 1-ETHYL-PYRROLIDINE-2,5-DIONE


Mass: 127.141 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H9NO2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 493 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
Nonpolymer details1-ETHYLPYRROLE-2,5-DIONE (NEQ): THE LIGAND IS COVALENTLY ATTACHED TO THE R CYS118

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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: 3.57 Å3/Da / Density % sol: 65.59 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.072
DetectorDate: Apr 8, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.072 Å / Relative weight: 1
ReflectionResolution: 2.17→119.82 Å / Num. obs: 59613 / % possible obs: 100 % / Observed criterion σ(I): 0 / Redundancy: 13.9 % / Biso Wilson estimate: 39.18 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 33.2
Reflection shellResolution: 2.17→2.29 Å / Redundancy: 14.1 % / Rmerge(I) obs: 0.48 / Mean I/σ(I) obs: 6.4 / % possible all: 100

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Processing

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

1bkd


Resolution: 2.17→119.82 Å / Cor.coef. Fo:Fc: 0.9413 / Cor.coef. Fo:Fc free: 0.9274 / SU R Cruickshank DPI: 0.228 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.157 / SU Rfree Blow DPI: 0.141 / SU Rfree Cruickshank DPI: 0.141
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. RESIDUE TYPES WITHOUT CCP4 ATOM TYPE IN LIBRARY=. NUMBER OF ATOMS WITH PROPER CCP4 ATOM TYPE=10570. NUMBER WITH APPROX DEFAULT CCP4 ATOM TYPE=0. NUMBER ...Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. RESIDUE TYPES WITHOUT CCP4 ATOM TYPE IN LIBRARY=. NUMBER OF ATOMS WITH PROPER CCP4 ATOM TYPE=10570. NUMBER WITH APPROX DEFAULT CCP4 ATOM TYPE=0. NUMBER TREATED BY BAD NON-BONDED CONTACTS=3.
RfactorNum. reflection% reflectionSelection details
Rfree0.2123 3013 5.05 %RANDOM
Rwork0.1856 ---
obs0.187 59613 99.38 %-
Displacement parametersBiso mean: 42.1 Å2
Baniso -1Baniso -2Baniso -3
1-0.2049 Å20 Å20 Å2
2--0.2049 Å20 Å2
3----0.4098 Å2
Refine analyzeLuzzati coordinate error obs: 0.222 Å
Refinement stepCycle: LAST / Resolution: 2.17→119.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5063 0 9 493 5565
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0110188HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0118428HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2256SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes143HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1456HARMONIC5
X-RAY DIFFRACTIONt_it10188HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.46
X-RAY DIFFRACTIONt_other_torsion15.96
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion675SEMIHARMONIC5
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_contact11212SEMIHARMONIC4
LS refinement shellResolution: 2.17→2.23 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2066 197 4.9 %
Rwork0.1801 3823 -
all0.1814 4020 -
obs--99.38 %

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