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- PDB-7mqu: The haddock model of GDP KRas in complex with promethazine using ... -

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Basic information

Entry
Database: PDB / ID: 7mqu
TitleThe haddock model of GDP KRas in complex with promethazine using NMR chemical shift perturbations
ComponentsGTPase KRas
KeywordsHYDROLASE/HYDROLASE inhibitor / KRas / allosteric inhibitor / drug discovery / HADDOCK / HYDROLASE-HYDROLASE inhibitor complex
Function / homology
Function and homology information


forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Rac protein signal transduction / skeletal muscle cell differentiation / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants ...forebrain astrocyte development / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / type I pneumocyte differentiation / Rac protein signal transduction / skeletal muscle cell differentiation / positive regulation of Rac protein signal transduction / 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 / RUNX3 regulates p14-ARF / SOS-mediated signalling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / Signalling to RAS / SHC-related events triggered by IGF1R / glial cell proliferation / Activated NTRK2 signals through FRS2 and FRS3 / 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 / SHC-mediated cascade:FGFR2 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / positive regulation of glial cell proliferation / Signaling by FLT3 ITD and TKD mutants / homeostasis of number of cells within a tissue / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / Tie2 Signaling / FRS-mediated FGFR1 signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / Ras activation upon Ca2+ influx through NMDA receptor / Signaling by FGFR1 in disease / GRB2 events in ERBB2 signaling / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / Insulin receptor signalling cascade / small monomeric GTPase / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / G protein activity / VEGFR2 mediated cell proliferation / FCERI mediated MAPK activation / Signaling by ERBB2 TMD/JMD mutants / regulation of long-term neuronal synaptic plasticity / RAF activation / Signaling by high-kinase activity BRAF mutants / Constitutive Signaling by EGFRvIII / visual learning / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / Signaling by SCF-KIT / cytoplasmic side of plasma membrane / Regulation of RAS by GAPs / Negative regulation of MAPK pathway / RAS processing / 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 CSF1 (M-CSF) in myeloid cells / MAPK cascade / Signaling by BRAF and RAF1 fusions / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / DAP12 signaling / Ca2+ pathway / gene expression / actin cytoskeleton organization / RAF/MAP kinase cascade / neuron apoptotic process / mitochondrial outer membrane / negative regulation of neuron apoptotic process / Ras protein signal transduction / positive regulation of protein phosphorylation / Golgi membrane / focal adhesion
Similarity search - Function
Small GTPase, Ras-type / small GTPase Ras family profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / 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 nucleoside triphosphate hydrolase
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / Chem-ZM7 / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodSOLUTION NMR / torsion angle dynamics
AuthorsWang, X. / Gorfe, A.A. / Putkey, J.P.
Funding support United States, 1items
OrganizationGrant numberCountry
Other privateCPRIT Grant No DP150093 United States
CitationJournal: J.Biomol.Nmr / Year: 2021
Title: Antipsychotic phenothiazine drugs bind to KRAS in vitro.
Authors: Wang, X. / Gorfe, A.A. / Putkey, J.A.
History
DepositionMay 6, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 11, 2022Provider: repository / Type: Initial release
Revision 1.1May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2 / Item: _database_2.pdbx_DOI

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Structure visualization

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MolmilJmol/JSmol

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Assembly

Deposited unit
A: GTPase KRas
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,0244
Polymers19,2721
Non-polymers7523
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area860 Å2
ΔGint-18 kcal/mol
Surface area8420 Å2
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)5 / 1000structures with the lowest energy
RepresentativeModel #1lowest energy

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Components

#1: Protein GTPase KRas / K-Ras 2 / Ki-Ras / c-K-ras / c-Ki-ras


Mass: 19271.760 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KRAS, KRAS2, RASK2 / Production host: Escherichia coli (E. coli) / References: UniProt: P01116, small monomeric GTPase
#2: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-ZM7 / (2R)-N,N-dimethyl-1-(10H-phenothiazin-10-yl)propan-2-amine


Mass: 284.419 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H20N2S
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: SOLUTION NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDSample stateSpectrometer-IDType
111isotropic13D HN(CA)CB
121isotropic13D CBCA(CO)NH
131isotropic12D 1H-15N HSQC
141isotropic13D 1H-15N NOESY
252isotropic12D 1H-13C HSQC

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Sample preparation

Details
TypeSolution-IDContentsDetailsLabelSolvent system
solution10.8 mM [U-99% 13C; U-99% 15N] GTPase KRas, 1.0 mM PMZ, 5 mM [U-99% 2H] DTT, 25 mM sodium phosphate, 50 mM sodium chloride, 10 uM [U-99% 2H] DSS, 5 mM MAGNESIUM ION, 95% H2O/5% D2O25 mM sodium phosphate, 50 mM NaCl, 5 mM MgCl2, 5 mM d10 DTT, and 10 microM DSS, 95% H2O/5% D2O.GDP KRas_PMZ_H2O95% H2O/5% D2O
solution20.8 mM [U-99% 13C; U-99% 15N] GTPase KRas, 1.0 mM PMZ, 5 mM [U-99% 2H] DTT, 25 mM sodium phosphate, 50 mM sodium chloride, 5 mM MAGNESIUM ION, 10 uM [U-99% 2H] DSS, 100% D2O25 mM sodium phosphate, 50 mM NaCl, 5 mM MgCl2, 5 mM d10 DTT, and 10 microM DSS, 99.99% D2O.GDP KRas_PMZ_D2O100% D2O
Sample
Conc. (mg/ml)ComponentIsotopic labelingSolution-ID
0.8 mMGTPase KRas[U-99% 13C; U-99% 15N]1
1.0 mMPMZnatural abundance1
5 mMDTT[U-99% 2H]1
25 mMsodium phosphatenatural abundance1
50 mMsodium chloridenatural abundance1
10 uMDSS[U-99% 2H]1
5 mMMAGNESIUM IONnatural abundance1
0.8 mMGTPase KRas[U-99% 13C; U-99% 15N]2
1.0 mMPMZnatural abundance2
5 mMDTT[U-99% 2H]2
25 mMsodium phosphatenatural abundance2
50 mMsodium chloridenatural abundance2
5 mMMAGNESIUM IONnatural abundance2
10 uMDSS[U-99% 2H]2
Sample conditions
Conditions-IDIonic strengthLabelpHPressure (kPa)Temperature (K)
1115 mMGDP KRas_PMZ_H2O7.4 1 Pa298 K
2115 mMGDP KRas_PMZ_D2O7.4 pD1 Pa298 K

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NMR measurement

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

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Processing

NMR software
NameDeveloperClassification
TopSpinBruker Biospincollection
HADDOCKBonvinstructure calculation
NMRPipeDelaglio, Grzesiek, Vuister, Zhu, Pfeifer and Baxprocessing
NMRViewJJohnson, One Moon Scientificpeak picking
RefinementMethod: torsion angle dynamics / Software ordinal: 2
NMR representativeSelection criteria: lowest energy
NMR ensembleConformer selection criteria: structures with the lowest energy
Conformers calculated total number: 1000 / Conformers submitted total number: 5

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