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- PDB-7lgi: The haddock model of GDP KRas in complex with promazine using che... -

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Basic information

Entry
Database: PDB / ID: 7lgi
TitleThe haddock model of GDP KRas in complex with promazine using chemical shift perturbations and intermolecular NOEs
ComponentsGTPase KRas
KeywordsHYDROLASE / GDP KRAS / SMALL MOLECULE LIGAND / HADDOCK STRUCTURE MODEL / CHEMICAL SHIFT CHANGES / INTERMOLECULAR NOE
Function / homology
Function and homology information


GMP binding / response to mineralocorticoid / forebrain astrocyte development / LRR domain binding / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis ...GMP binding / response to mineralocorticoid / forebrain astrocyte development / LRR domain binding / negative regulation of epithelial cell differentiation / response to isolation stress / response to gravity / type I pneumocyte differentiation / regulation of synaptic transmission, GABAergic / epithelial tube branching involved in lung morphogenesis / Rac protein signal transduction / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / myoblast proliferation / skeletal muscle cell differentiation / 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 / cardiac muscle cell proliferation / Signalling to RAS / Activated NTRK2 signals through FRS2 and FRS3 / SHC-related events triggered by IGF1R / Estrogen-stimulated signaling through PRKCZ / glial cell proliferation / 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 CSF3 (G-CSF) / 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 / striated muscle cell differentiation / Signaling by FGFR2 in disease / positive regulation of glial cell proliferation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / Signaling by FGFR1 in disease / EGFR Transactivation by Gastrin / NCAM signaling for neurite out-growth / homeostasis of number of cells within a tissue / CD209 (DC-SIGN) signaling / GRB2 events in ERBB2 signaling / Downstream signal transduction / Ras activation upon Ca2+ influx through NMDA receptor / SHC1 events in ERBB2 signaling / Insulin receptor signalling cascade / response to glucocorticoid / Constitutive Signaling by Overexpressed ERBB2 / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / VEGFR2 mediated cell proliferation / small monomeric GTPase / FCERI mediated MAPK activation / female pregnancy / RAF activation / liver development / Signaling by ERBB2 TMD/JMD mutants / Signaling by high-kinase activity BRAF mutants / regulation of long-term neuronal synaptic plasticity / Signaling by SCF-KIT / Constitutive Signaling by EGFRvIII / MAP2K and MAPK activation / Signaling by ERBB2 ECD mutants / visual learning / Signaling by ERBB2 KD Mutants / Signaling by CSF1 (M-CSF) in myeloid cells / RAS processing / Regulation of RAS by GAPs / Negative regulation of MAPK pathway / cytoplasmic side of plasma membrane / cytokine-mediated signaling pathway / 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 / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / positive regulation of cellular senescence / MAPK cascade / DAP12 signaling
Similarity search - Function
Small GTPase, Ras-type / Small GTPase Ras domain 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 nucleotide triphosphate hydrolases ...Small GTPase, Ras-type / Small GTPase Ras domain 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 nucleotide triphosphate hydrolases / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / Promazine / GTPase KRas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodSOLUTION NMR / simulated annealing
AuthorsWang, X. / Gorfe, A.A. / Putkey, J.A.
Funding support United States, 1items
OrganizationGrant numberCountry
Cancer Prevention and Research Institute of Texas (CPRIT)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
DepositionJan 20, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 21, 2021Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
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
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)10 / 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-P2Z / Promazine / N,N-dimethyl-3-(10H-phenothiazin-10-yl)propan-1-amine


Mass: 284.419 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H20N2S / Feature type: SUBJECT OF INVESTIGATION
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
111isotropic12D 1H-15N HSQC
121isotropic13D CBCA(CO)NH
131isotropic13D HN(CA)CB
141isotropic13D C(CO)NH
151isotropic13D H(CCO)NH
262isotropic12D 1H-13C HSQC
272isotropic13D CCH-TOCSY
282isotropic13D 1H-13C NOESY aliphatic
292isotropic115N-FILTERED 3D NOESY- 1H
2102isotropic12D 1H-13C HSQC aliphatic

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Sample preparation

Details
TypeSolution-IDContentsDetailsLabelSolvent system
solution10.8 mM [U-99% 13C; U-99% 15N] KRAS, 1.0 mM P2Z, 5 mM [U-99% 2H] DTT, 10 uM [U-99% 2H] DSS, 25 mM sodium phosphate, 50 mM sodium chloride, 90% H2O/10% D2O0.8 mM [U-99% 13C; U-99% 15N] KRAS, 1.0 mM P2Z, 5 mM [U-99% 2H] DTT, 10 uM [U-99% 2H] DSS, 25 mM nature abundance sodium phosphate, 50 mM sodium chloride, 5 mM MAGNESIUM ION, 95% H2O/5% D2OKRas_P2Z_H2O90% H2O/10% D2O
solution20.8 mM [U-99% 13C; U-99% 15N] KRAS, 1.0 mM P2Z, 5 mM [U-99% 2H] DTT, 10 uM [U-99% 2H] DSS, 25 mM sodium phosphate, 50 mM sodium chloride, 100% D2O0.8 mM [U-99% 13C; U-99% 15N] KRas, 1.0 mM P2Z, 5 mM [U-99% 2H] DTT, 10 uM [U-99% 2H] DSS, 25 mM sodium phosphate, 50 mM sodium chloride, 5 mM MAGNESIUM ION, 100% D2OKRas_P2Z_D2O100% D2O
Sample
Conc. (mg/ml)ComponentIsotopic labelingSolution-ID
0.8 mMKRAS[U-99% 13C; U-99% 15N]1
1.0 mMP2Znatural abundance1
5 mMDTT[U-99% 2H]1
10 uMDSS[U-99% 2H]1
25 mMsodium phosphatenatural abundance1
50 mMsodium chloridenatural abundance1
0.8 mMKRAS[U-99% 13C; U-99% 15N]2
1.0 mMP2Znatural abundance2
5 mMDTT[U-99% 2H]2
10 uMDSS[U-99% 2H]2
25 mMsodium phosphatenatural abundance2
50 mMsodium chloridenatural abundance2
Sample conditions
Conditions-IDIonic strengthLabelpHPressure (kPa)Temperature (K)
1115 mMH2O7.41 PA atm298 K
2115 mMD2O7.4 pD1 PA atm298 K

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NMR measurement

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

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Processing

NMR software
NameVersionDeveloperClassification
TopSpin1.3Bruker Biospincollection
NMRPipe2.2Delaglio, Grzesiek, Vuister, Zhu, Pfeifer and Baxprocessing
NMRViewJJohnson, One Moon Scientificdata analysis
HADDOCKA.M.J.J. Bonvinrefinement
RefinementMethod: simulated annealing / Software ordinal: 4
NMR representativeSelection criteria: lowest energy
NMR ensembleConformer selection criteria: structures with the lowest energy
Conformers calculated total number: 1000 / Conformers submitted total number: 10

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