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- PDB-5zc6: Solution structure of H-RasT35S mutant protein in complex with KBFM123 -

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Basic information

Entry
Database: PDB / ID: 5zc6
TitleSolution structure of H-RasT35S mutant protein in complex with KBFM123
ComponentsGTPase HRas
KeywordsONCOPROTEIN / Inhibitor / Complex / Cancer / Small GTPases
Function / homology
Function and homology information


phospholipase C activator activity / GTPase complex / oncogene-induced cell senescence / negative regulation of GTPase activity / 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 ...phospholipase C activator activity / GTPase complex / oncogene-induced cell senescence / negative regulation of GTPase activity / 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 / positive regulation of MAP kinase activity / 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 / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR4 / Erythropoietin activates RAS / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / protein-membrane adaptor activity / Signaling by FGFR3 in disease / p38MAPK events / FRS-mediated FGFR1 signaling / Tie2 Signaling / Signaling by FGFR2 in disease / positive regulation of GTPase activity / EPHB-mediated forward signaling / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / myelination / 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 / Ras activation upon Ca2+ influx through NMDA receptor / intrinsic apoptotic signaling pathway / SHC1 events in ERBB2 signaling / Insulin receptor signalling cascade / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / positive regulation of epithelial cell proliferation / VEGFR2 mediated cell proliferation / animal organ morphogenesis / small monomeric GTPase / regulation of actin cytoskeleton organization / FCERI mediated MAPK activation / positive regulation of JNK cascade / RAF activation / Signaling by ERBB2 TMD/JMD mutants / Signaling by high-kinase activity BRAF mutants / regulation of long-term neuronal synaptic plasticity / cellular response to gamma radiation / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / RAS processing / Regulation of RAS by GAPs / Negative regulation of MAPK pathway / positive regulation of type II interferon production / endocytosis / positive regulation of fibroblast proliferation / chemotaxis / 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 / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / MAPK cascade / insulin receptor signaling pathway / DAP12 signaling
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 nucleotide triphosphate hydrolases / Rossmann fold ...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 nucleotide triphosphate hydrolases / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / Chem-KBF / GTPase HRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodSOLUTION NMR / simulated annealing
AuthorsMatsumoto, S. / Hayashi, Y. / Hiraga, T. / Matsuo, K. / Kataoka, T.
Funding support Japan, 2items
OrganizationGrant numberCountry
the Ministry of Health, Labor and Welfare and Japan Agency for Medical Research and Development15ak0101006h0005 Japan
the National Institute of Biomedical Innovation and Japan Agency for Medical Research and Development15nk0101401h0002 Japan
CitationJournal: Biochemistry / Year: 2018
Title: Molecular Basis for Allosteric Inhibition of GTP-Bound H-Ras Protein by a Small-Molecule Compound Carrying a Naphthalene Ring
Authors: Matsumoto, S. / Hiraga, T. / Hayashi, Y. / Yoshikawa, Y. / Tsuda, C. / Araki, M. / Neya, M. / Shima, F. / Kataoka, T.
History
DepositionFeb 15, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 12, 2018Provider: repository / Type: Initial release
Revision 1.1Sep 26, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2May 1, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_nmr_spectrometer
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_nmr_spectrometer.model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: GTPase HRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,6794
Polymers18,8611
Non-polymers8183
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area860 Å2
ΔGint-12 kcal/mol
Surface area8440 Å2
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)15 / 100structures with the lowest energy
RepresentativeModel #1lowest energy

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Components

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


Mass: 18861.166 Da / Num. of mol.: 1 / Fragment: UNP residues 1-166 / Mutation: T35S
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: 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
#3: Chemical ChemComp-KBF / 3-oxidanyl-~{N}-[[(2~{R})-oxolan-2-yl]methyl]naphthalene-2-carboxamide / 3-hydroxy-N-(tetrahydrofuran-2-ylmethyl)naphthalene-2-carboxamide


Mass: 271.311 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H17NO3
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg

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Experimental details

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Experiment

ExperimentMethod: SOLUTION NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDSample stateSpectrometer-IDType
111isotropic12D 1H-1H NOESY
121isotropic13D 1H-13C NOESY
131isotropic12D 1H-13C HSQC aliphatic

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Sample preparation

DetailsType: solution
Contents: 0.8 mM [U-99% 13C; U-99% 15N] H-RasT35S, 3.0 mM KBFM123, 20 mM sodium phosphate, 40 mM sodium chloride, 8 mM MAGNESIUM ION, 0.8 mM PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, 80% D2O/20% d6-DMSO
Label: sample_1 / Solvent system: 80% D2O/20% d6-DMSO
Sample
Conc. (mg/ml)ComponentIsotopic labelingSolution-ID
0.8 mMH-RasT35S[U-99% 13C; U-99% 15N]1
3.0 mMKBFM123natural abundance1
20 mMsodium phosphatenatural abundance1
40 mMsodium chloridenatural abundance1
8 mMMAGNESIUM IONnatural abundance1
0.8 mMPHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTERnatural abundance1
Sample conditionsIonic strength: 50 mM / Label: conditions_1 / pH: 6.8 / Pressure: ambient Pa / Temperature: 278 K

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NMR measurement

NMR spectrometerType: Bruker AVANCE III / Manufacturer: Bruker / Model: AVANCE III / Field strength: 600 MHz

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Processing

NMR softwareName: CNS / Developer: BRUNGER A. T. ET.AL. / Classification: refinement
RefinementMethod: simulated annealing / Software ordinal: 1
NMR representativeSelection criteria: lowest energy
NMR ensembleConformer selection criteria: structures with the lowest energy
Conformers calculated total number: 100 / Conformers submitted total number: 15

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