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- PDB-3f82: Crystal structure of the tyrosine kinase domain of the hepatocyte... -

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Basic information

Entry
Database: PDB / ID: 3f82
TitleCrystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor C-MET in complex with N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide
Componentshepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE / Alternative splicing / RECEPTOR TYROSINE KINASE / SIGNAL TRANSDUCTION / GRB2 / SHC / ATP-BINDING / GLYCOPROTEIN / MEMBRANE / NUCLEOTIDE-BINDING / PHOSPHOPROTEIN / PROTO-ONCOGENE / TRANSMEMBRANE / TYROSINE-PROTEIN KINASE
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-353 / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsSack, J.
CitationJournal: J.Med.Chem. / Year: 2009
Title: Discovery of N-(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a Selective and Orally Efficacious ...Title: Discovery of N-(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a Selective and Orally Efficacious Inhibitor of the Met Kinase Superfamily
Authors: Schroeder, G.M. / An, Y. / Cai, Z.W. / Chen, X.T. / Clark, C. / Cornelius, L.A. / Dai, J. / Gullo-Brown, J. / Gupta, A. / Henley, B. / Hunt, J.T. / Jeyaseelan, R. / Kamath, A. / Kim, K. / ...Authors: Schroeder, G.M. / An, Y. / Cai, Z.W. / Chen, X.T. / Clark, C. / Cornelius, L.A. / Dai, J. / Gullo-Brown, J. / Gupta, A. / Henley, B. / Hunt, J.T. / Jeyaseelan, R. / Kamath, A. / Kim, K. / Lippy, J. / Lombardo, L.J. / Manne, V. / Oppenheimer, S. / Sack, J.S. / Schmidt, R.J. / Shen, G. / Stefanski, K. / Tokarski, J.S. / Trainor, G.L. / Wautlet, B.S. / Wei, D. / Williams, D.K. / Zhang, Y. / Zhang, Y. / Fargnoli, J. / Borzilleri, R.M.
History
DepositionNov 11, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 31, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 20, 2021Group: Database references / Category: database_2 / struct_ref_seq_dif
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details

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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)35,9482
Polymers35,4351
Non-polymers5131
Water2,288127
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.670, 46.883, 157.650
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 / E.C.2.7.10.1 / HGF RECEPTOR / SCATTER FACTOR RECEPTOR / SF RECEPTOR / HGF/SF RECEPTOR / MET PROTO-ONCOGENE ...HGF RECEPTOR / SCATTER FACTOR RECEPTOR / SF RECEPTOR / HGF/SF RECEPTOR / MET PROTO-ONCOGENE TYROSINE KINASE / C-MET


Mass: 35435.031 Da / Num. of mol.: 1 / Fragment: RESIDUES 1049-1360 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-353 / N-{4-[(2-amino-3-chloropyridin-4-yl)oxy]-3-fluorophenyl}-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide


Mass: 512.893 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H19ClF2N4O4
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 127 / 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: 44.72 %
Crystal growpH: 7.1 / Details: 12% MEPEG 5000, 0.1M HEPES (PH 7.1) 11% 2-PROPANOL

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Aug 17, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→25 Å / Num. obs: 11610 / % possible obs: 99.4 % / Observed criterion σ(I): 0 / Redundancy: 4.3 % / Biso Wilson estimate: 39.628 Å2 / Rmerge(I) obs: 0.079 / Net I/σ(I): 17.3
Reflection shellResolution: 2.5→2.59 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.275 / Mean I/σ(I) obs: 4.2 / % possible all: 97.2

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Processing

Software
NameVersionClassification
AMoREphasing
BUSTER-TNT2.5.1refinement
HKL-2000(DENZO)data reduction
HKL-2000(SCALEPACK)data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: MET KINASE COMPLEXED WITH BMS-758982

Resolution: 2.5→16.54 Å / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2533 547 4.79 %RANDOM
Rwork0.18 ---
all0.1834 11431 --
obs0.1834 11431 99.31 %-
Displacement parametersBiso mean: 30.91 Å2
Baniso -1Baniso -2Baniso -3
1-3.44456646 Å20 Å20 Å2
2---0.2538769 Å20 Å2
3----3.19068956 Å2
Refinement stepCycle: LAST / Resolution: 2.5→16.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2169 0 36 127 2332
Refine LS restraints
Refine-IDTypeDev idealNumberWeight
X-RAY DIFFRACTIONt_bond_d0.00622612
X-RAY DIFFRACTIONt_angle_deg0.86830542
X-RAY DIFFRACTIONt_dihedral_angle_d21.3614220
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes0.006402
X-RAY DIFFRACTIONt_gen_planes0.013265
X-RAY DIFFRACTIONt_it1.319226120
X-RAY DIFFRACTIONt_nbd0.032295
LS refinement shellResolution: 2.5→2.65 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.2578 80 4.54 %
Rwork0.1825 1682 -
all0.186 1762 -
obs--99.31 %

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