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- PDB-5hor: Crystal structure of c-Met-M1250T in complex with SAR125844. -

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Basic information

Entry
Database: PDB / ID: 5hor
TitleCrystal structure of c-Met-M1250T in complex with SAR125844.
ComponentsHepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE / inhibitor
Function / homology
Function and homology information


hepatocyte growth factor receptor activity / Drug-mediated inhibition of MET activation / MET activates STAT3 / endothelial cell morphogenesis / negative regulation of hydrogen peroxide-mediated programmed cell death / negative regulation of guanyl-nucleotide exchange factor activity / MET interacts with TNS proteins / MET Receptor Activation / positive regulation of endothelial cell chemotaxis / semaphorin receptor activity ...hepatocyte growth factor receptor activity / Drug-mediated inhibition of MET activation / MET activates STAT3 / endothelial cell morphogenesis / negative regulation of hydrogen peroxide-mediated programmed cell death / negative regulation of guanyl-nucleotide exchange factor activity / MET interacts with TNS proteins / MET Receptor Activation / positive regulation of endothelial cell chemotaxis / semaphorin receptor activity / MET receptor recycling / Sema4D mediated inhibition of cell attachment and migration / MET activates PTPN11 / pancreas development / negative regulation of Rho protein signal transduction / MET activates PI3K/AKT signaling / MET activates RAP1 and RAC1 / negative regulation of stress fiber assembly / negative regulation of thrombin-activated receptor signaling pathway / semaphorin-plexin signaling pathway / MET activates PTK2 signaling / branching morphogenesis of an epithelial tube / positive chemotaxis / establishment of skin barrier / MECP2 regulates neuronal receptors and channels / positive regulation of microtubule polymerization / MET activates RAS signaling / phagocytosis / negative regulation of autophagy / basal plasma membrane / InlB-mediated entry of Listeria monocytogenes into host cell / liver development / Negative regulation of MET activity / neuron differentiation / receptor protein-tyrosine kinase / transmembrane receptor protein tyrosine kinase activity / positive regulation of kinase activity / Constitutive Signaling by Aberrant PI3K in Cancer / PIP3 activates AKT signaling / nervous system development / transmembrane receptor protein tyrosine kinase signaling pathway / cell migration / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein tyrosine kinase activity / positive regulation of protein kinase B signaling / protein phosphatase binding / cell surface receptor signaling pathway / receptor complex / cell surface / signal transduction / plasma membrane => GO:0005886 / positive regulation of transcription by RNA polymerase II / extracellular region / membrane => GO:0016020 / ATP binding / identical protein binding / plasma membrane
Similarity search - Function
Tyrosine-protein kinase, HGF/MSP receptor / Plexin family / Plexin repeat / Plexin repeat / Sema domain / semaphorin domain / Sema domain superfamily / Sema domain profile. / Sema domain / IPT/TIG domain ...Tyrosine-protein kinase, HGF/MSP receptor / Plexin family / Plexin repeat / Plexin repeat / Sema domain / semaphorin domain / Sema domain superfamily / Sema domain profile. / Sema domain / IPT/TIG domain / ig-like, plexins, transcription factors / PSI domain / domain found in Plexins, Semaphorins and Integrins / IPT domain / Immunoglobulin E-set / Tyrosine kinase, catalytic domain / Tyrosine-protein kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / WD40/YVTN repeat-like-containing domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Protein kinases ATP-binding region signature. / Protein kinase, ATP binding site / 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-63K / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.2 Å
AuthorsVallee, F. / Houtmann, J. / Marquette, J.-P.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Discovery and Pharmacokinetic and Pharmacological Properties of the Potent and Selective MET Kinase Inhibitor 1-{6-[6-(4-Fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]benzothiazol- ...Title: Discovery and Pharmacokinetic and Pharmacological Properties of the Potent and Selective MET Kinase Inhibitor 1-{6-[6-(4-Fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]benzothiazol-2-yl}-3-(2-morpholin-4-ylethyl)urea (SAR125844).
Authors: Ugolini, A. / Kenigsberg, M. / Rak, A. / Vallee, F. / Houtmann, J. / Lowinski, M. / Capdevila, C. / Khider, J. / Albert, E. / Martinet, N. / Nemecek, C. / Grapinet, S. / Bacque, E. / ...Authors: Ugolini, A. / Kenigsberg, M. / Rak, A. / Vallee, F. / Houtmann, J. / Lowinski, M. / Capdevila, C. / Khider, J. / Albert, E. / Martinet, N. / Nemecek, C. / Grapinet, S. / Bacque, E. / Roesner, M. / Delaisi, C. / Calvet, L. / Bonche, F. / Semiond, D. / Egile, C. / Goulaouic, H. / Schio, L.
History
DepositionJan 19, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Nov 23, 2016Provider: repository / Type: Initial release
Revision 1.1Oct 24, 2018Group: Data collection / Source and taxonomy / Structure summary
Category: entity / entity_src_gen / entity_src_nat / Item: _entity.src_method
Revision 1.2Oct 16, 2019Group: Data collection / Category: reflns_shell

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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)35,8272
Polymers35,2771
Non-polymers5511
Water1,71195
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)43.020, 46.990, 156.620
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Hepatocyte growth factor receptor / C-Met / 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: 35276.805 Da / Num. of mol.: 1 / Mutation: M1250T,Y1194F,Y1234F,Y1235D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-63K / 1-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea


Mass: 550.631 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H23FN8O2S2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 95 / 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: 2.24 Å3/Da / Density % sol: 45.13 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: Tris 100mM, MPD 20%, pH8.5 / PH range: 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.0723 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 15, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0723 Å / Relative weight: 1
ReflectionResolution: 2.2→39.1 Å / Num. obs: 16185 / % possible obs: 99.6 % / Redundancy: 4.3 % / Net I/σ(I): 13.5

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Processing

Software
NameClassification
BUSTER-TNTrefinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementResolution: 2.2→39.1 Å / Cross valid method: FREE R-VALUE /
Num. reflection% reflection
obs16185 96.1 %
Refinement stepCycle: LAST / Resolution: 2.2→39.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1956 0 38 95 2089

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