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- PDB-4nyi: Approach for Targeting Ras with Small Molecules that Activate SOS... -

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Basic information

Entry
Database: PDB / ID: 4nyi
TitleApproach for Targeting Ras with Small Molecules that Activate SOS-Mediated Nucleotide Exchange
Components
  • (GTPase HRas) x 2
  • Son of sevenless homolog 1
KeywordsSIGNALING PROTEIN / Ras SOS complex / signal transduction / Raf / PI3K / poly-petide / cytosol
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 / Regulation of KIT signaling / NRAGE signals death through JNK / epidermal growth factor receptor binding / 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 / hair follicle development / SHC1 events in ERBB4 signaling / 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 / adipose tissue development / Signal attenuation / 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 / EPHB-mediated forward signaling / Signaling by FLT3 fusion proteins / RAC1 GTPase cycle / myelination / Signaling by FGFR1 in disease / intrinsic apoptotic signaling pathway / 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 / GTPase activator activity / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / 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-2PX / 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: 2.9612 Å
AuthorsBurns, M.C. / Sun, Q. / Phan, J. / Fesik, S.W.
CitationJournal: Proc.Natl.Acad.Sci.USA / 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
DepositionDec 10, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 12, 2014Provider: repository / Type: Initial release
Revision 1.1Mar 19, 2014Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
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_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.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_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.value / _struct_conn.pdbx_dist_value / _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_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_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)95,2816
Polymers94,3053
Non-polymers9763
Water2,594144
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7690 Å2
ΔGint-27 kcal/mol
Surface area35540 Å2
MethodPISA
Unit cell
Length a, b, c (Å)183.285, 183.285, 177.860
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number97
Space group name H-MI422

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Components

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Protein , 3 types, 3 molecules QRS

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


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 / H-Ras-1 / Ha-Ras / Transforming protein p21 / c-H-ras / p21ras / GTPase HRas / N-terminally processed


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: 56532.730 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, 147 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


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-2PX / N-{1-[(5-methyl-1H-indol-3-yl)methyl]piperidin-4-yl}-L-tryptophanamide


Mass: 429.557 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H31N5O
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 144 / 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: 3.96 Å3/Da / Density % sol: 68.94 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4
Details: 0.1 M sodium acetate, 2.0 M sodium formate, pH 4.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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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: Dec 5, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.961→35.945 Å / Num. all: 31718 / Num. obs: 31718 / % possible obs: 100 %

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Processing

Software
NameVersionClassification
MAR345dtbdata collection
PHENIX(phenix.refine: 1.8.2_1309)model building
PHENIX(phenix.refine: 1.8.2_1309)refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIX1.8.2_1309phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.9612→35.945 Å / SU ML: 0.31 / σ(F): 0 / Phase error: 20.73 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2083 1580 4.98 %
Rwork0.1648 --
obs0.1669 31705 99.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.9612→35.945 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6564 0 65 144 6773
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0086799
X-RAY DIFFRACTIONf_angle_d1.1359204
X-RAY DIFFRACTIONf_dihedral_angle_d17.9472612
X-RAY DIFFRACTIONf_chiral_restr0.0751006
X-RAY DIFFRACTIONf_plane_restr0.0051195
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9612-3.05670.29191380.22992688X-RAY DIFFRACTION100
3.0567-3.16590.251390.212692X-RAY DIFFRACTION100
3.1659-3.29260.24211410.1982700X-RAY DIFFRACTION100
3.2926-3.44230.27671410.18932713X-RAY DIFFRACTION100
3.4423-3.62360.23421420.17542703X-RAY DIFFRACTION100
3.6236-3.85040.20841440.15872733X-RAY DIFFRACTION100
3.8504-4.14730.19171470.14142735X-RAY DIFFRACTION100
4.1473-4.56390.15791490.12782716X-RAY DIFFRACTION100
4.5639-5.22260.17921410.14242772X-RAY DIFFRACTION100
5.2226-6.57340.20391450.17892786X-RAY DIFFRACTION100
6.5734-35.94780.19481530.16012887X-RAY DIFFRACTION99

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