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- PDB-3dkf: Structure of MET receptor tyrosine kinase in complex with inhibit... -

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Basic information

Entry
Database: PDB / ID: 3dkf
TitleStructure of MET receptor tyrosine kinase in complex with inhibitor SGX-523
ComponentsHepatocyte growth factor receptor
KeywordsONCOPROTEIN / DRUG DISCOVERY / c-MET KINASE / FRAGMENT BASED / Membrane / Receptor / Transmembrane
Function / homology
Function and homology information


negative regulation of guanyl-nucleotide exchange factor activity / Drug-mediated inhibition of MET activation / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET Receptor Activation / MET interacts with TNS proteins / endothelial cell morphogenesis / semaphorin receptor activity / MET receptor recycling / pancreas development ...negative regulation of guanyl-nucleotide exchange factor activity / Drug-mediated inhibition of MET activation / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET Receptor Activation / MET interacts with TNS proteins / endothelial cell morphogenesis / semaphorin receptor activity / MET receptor recycling / pancreas development / MET activates PTPN11 / MET activates RAP1 and RAC1 / Sema4D mediated inhibition of cell attachment and migration / MET activates PI3K/AKT signaling / negative regulation of stress fiber assembly / positive regulation of endothelial cell chemotaxis / MET activates PTK2 signaling / branching morphogenesis of an epithelial tube / positive chemotaxis / negative regulation of Rho protein signal transduction / negative regulation of thrombin-activated receptor signaling pathway / semaphorin-plexin signaling pathway / establishment of skin barrier / MET activates RAS signaling / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / MECP2 regulates neuronal receptors and channels / positive regulation of microtubule polymerization / negative regulation of autophagy / cell surface receptor protein tyrosine kinase signaling pathway / liver development / molecular function activator activity / basal plasma membrane / InlB-mediated entry of Listeria monocytogenes into host cell / excitatory postsynaptic potential / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / Negative regulation of MET activity / neuron differentiation / Constitutive Signaling by Aberrant PI3K in Cancer / PIP3 activates AKT signaling / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / protein phosphatase binding / receptor complex / cell surface receptor signaling pathway / postsynapse / cell surface / signal transduction / positive regulation of transcription by RNA polymerase II / extracellular region / ATP binding / identical protein binding / membrane / plasma membrane
Similarity search - Function
Tyrosine-protein kinase, HGF/MSP receptor / Plexin family / Plexin repeat / Plexin repeat / Sema domain / semaphorin domain / Sema domain / Sema domain superfamily / Sema domain profile. / IPT/TIG domain ...Tyrosine-protein kinase, HGF/MSP receptor / Plexin family / Plexin repeat / Plexin repeat / Sema domain / semaphorin domain / Sema domain / Sema domain superfamily / Sema domain profile. / IPT/TIG domain / ig-like, plexins, transcription factors / IPT domain / PSI domain / domain found in Plexins, Semaphorins and Integrins / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Immunoglobulin E-set / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-SX8 / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.8 Å
AuthorsHendle, J.
CitationJournal: Mol.Cancer Ther. / Year: 2009
Title: SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo.
Authors: Buchanan, S.G. / Hendle, J. / Lee, P.S. / Smith, C.R. / Bounaud, P.Y. / Jessen, K.A. / Tang, C.M. / Huser, N.H. / Felce, J.D. / Froning, K.J. / Peterman, M.C. / Aubol, B.E. / Gessert, S.F. / ...Authors: Buchanan, S.G. / Hendle, J. / Lee, P.S. / Smith, C.R. / Bounaud, P.Y. / Jessen, K.A. / Tang, C.M. / Huser, N.H. / Felce, J.D. / Froning, K.J. / Peterman, M.C. / Aubol, B.E. / Gessert, S.F. / Sauder, J.M. / Schwinn, K.D. / Russell, M. / Rooney, I.A. / Adams, J. / Leon, B.C. / Do, T.H. / Blaney, J.M. / Sprengeler, P.A. / Thompson, D.A. / Smyth, L. / Pelletier, L.A. / Atwell, S. / Holme, K. / Wasserman, S.R. / Emtage, S. / Burley, S.K. / Reich, S.H.
History
DepositionJun 24, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 7, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Apr 22, 2015Group: Structure summary
Revision 1.3Feb 10, 2021Group: Database references / Derived calculations
Category: citation_author / struct_ref_seq_dif / struct_site
Item: _citation_author.identifier_ORCID / _struct_ref_seq_dif.details ..._citation_author.identifier_ORCID / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Feb 21, 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: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,1453
Polymers35,7501
Non-polymers3952
Water3,837213
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)43.089, 46.679, 158.482
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Hepatocyte growth factor receptor / HGF receptor / HGF/SF receptor / Proto-oncogene c-Met / Scatter factor receptor / SF receptor / ...HGF receptor / HGF/SF receptor / Proto-oncogene c-Met / Scatter factor receptor / SF receptor / Tyrosine-protein kinase Met


Mass: 35750.348 Da / Num. of mol.: 1 / Mutation: Y1194F, Y1234F, Y1235D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET, hCG_38705, tcag7.66 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P08581
#2: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-SX8 / 6-{[6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}quinoline


Mass: 359.408 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H13N7S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 213 / 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: 2.23 Å3/Da / Density % sol: 44.82 %
Crystal growTemperature: 292 K / Method: vapor diffusion / pH: 7.5
Details: 20% ISOPROPANOL, 200 mM AMMONIUM ACETATE, 100 mM TRIS, pH 7.5, VAPOR DIFFUSION, temperature 292K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97969 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Jan 19, 2007
RadiationMonochromator: DIAMOND / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97969 Å / Relative weight: 1
ReflectionResolution: 1.8→34.986 Å / Num. obs: 24264 / % possible obs: 79.7 % / Redundancy: 4.3 % / Rmerge(I) obs: 0.055 / Net I/σ(I): 11.3

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Processing

Software
NameVersionClassificationNB
SCALA3.2.5data scaling
REFMACrefinement
PDB_EXTRACT3.006data extraction
RefinementResolution: 1.8→34.986 Å / Occupancy max: 1 / Occupancy min: 0.35 /
RfactorNum. reflection
Rfree0.233 -
Rwork0.191 -
obs-24264
Displacement parametersBiso max: 70.78 Å2 / Biso mean: 28.781 Å2 / Biso min: 5.17 Å2
Refinement stepCycle: LAST / Resolution: 1.8→34.986 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2263 0 27 213 2503

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