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- PDB-3ce3: Crystal structure of the tyrosine kinase domain of the hepatocyte... -

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Basic information

Entry
Database: PDB / ID: 3ce3
TitleCrystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor C-MET in complex with a Pyrrolopyridinepyridone based inhibitor
ComponentsHepatocyte growth factor receptor
KeywordsTRANSFERASE / 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 / 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 interacts with TNS proteins / MET Receptor Activation / endothelial cell morphogenesis / semaphorin receptor activity / MET receptor recycling ...hepatocyte growth factor receptor activity / 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 interacts with TNS proteins / MET Receptor Activation / 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 / negative regulation of Rho protein signal transduction / MET activates PTK2 signaling / branching morphogenesis of an epithelial tube / positive chemotaxis / 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 / phagocytosis / MECP2 regulates neuronal receptors and channels / positive regulation of microtubule polymerization / negative regulation of autophagy / basal plasma membrane / InlB-mediated entry of Listeria monocytogenes into host cell / excitatory postsynaptic potential / liver development / molecular function activator activity / Negative regulation of MET activity / receptor protein-tyrosine kinase / neuron differentiation / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / PIP3 activates AKT signaling / nervous system development / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein tyrosine kinase activity / protein phosphatase binding / postsynapse / receptor complex / cell surface receptor signaling pathway / 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 / PSI domain / domain found in Plexins, Semaphorins and Integrins / IPT domain / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Immunoglobulin E-set / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-1FN / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsSack, J.
CitationJournal: J.Med.Chem. / Year: 2008
Title: Discovery of pyrrolopyridine-pyridone based inhibitors of Met kinase: synthesis, X-ray crystallographic analysis, and biological activities.
Authors: Kim, K.S. / Zhang, L. / Schmidt, R. / Cai, Z.W. / Wei, D. / Williams, D.K. / Lombardo, L.J. / Trainor, G.L. / Xie, D. / Zhang, Y. / An, Y. / Sack, J.S. / Tokarski, J.S. / Darienzo, C. / ...Authors: Kim, K.S. / Zhang, L. / Schmidt, R. / Cai, Z.W. / Wei, D. / Williams, D.K. / Lombardo, L.J. / Trainor, G.L. / Xie, D. / Zhang, Y. / An, Y. / Sack, J.S. / Tokarski, J.S. / Darienzo, C. / Kamath, A. / Marathe, P. / Zhang, Y. / Lippy, J. / Jeyaseelan, R. / Wautlet, B. / Henley, B. / Gullo-Brown, J. / Manne, V. / Hunt, J.T. / Fargnoli, J. / Borzilleri, R.M.
History
DepositionFeb 28, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 26, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 20, 2021Group: Database references / Derived calculations / Category: database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Feb 21, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)35,8932
Polymers35,4351
Non-polymers4581
Water1,17165
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)43.040, 49.137, 159.324
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 / 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: TYROSINE KINASE DOMAIN, UNP RESIDUES 1049-1360 / Mutation: Y1194F, Y1234F, Y1235D, V1272L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Cell line (production host): SPODOPTERA FRUGIPERDA 9 (Sf9) / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-1FN / 1-(4-fluorophenyl)-N-[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide


Mass: 458.416 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H16F2N4O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 65 / 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: 2.38 Å3/Da / Density % sol: 48.26 %
Crystal growpH: 7.1
Details: 12% MEPEG 5000, 0.1M HEPES, 11% 2-PROPANOL., pH 7.1

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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: Nov 27, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.4→50 Å / Num. obs: 10949 / % possible obs: 81.3 % / Observed criterion σ(I): 0 / Redundancy: 3.8 % / Biso Wilson estimate: 53.116 Å2 / Rmerge(I) obs: 0.144 / Net I/σ(I): 10
Reflection shellResolution: 2.4→2.49 Å / Redundancy: 2.4 % / Rmerge(I) obs: 0.467 / Mean I/σ(I) obs: 1.1 / % possible all: 69.9

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Processing

Software
NameVersionClassification
BUSTER-TNT2.1.1refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→50 Å / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2751 601 5.51 %RANDOM
Rwork0.2059 ---
obs0.2095 10915 78.52 %-
Displacement parametersBiso mean: 71.35 Å2
Baniso -1Baniso -2Baniso -3
1-15.86705709 Å20 Å20 Å2
2--7.80534152 Å20 Å2
3----23.67239861 Å2
Refinement stepCycle: LAST / Resolution: 2.4→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2323 0 34 65 2422
Refine LS restraints
Refine-IDTypeDev idealNumberWeight
X-RAY DIFFRACTIONt_bond_d0.00624182
X-RAY DIFFRACTIONt_angle_deg0.84832632
X-RAY DIFFRACTIONt_dihedral_angle_d24.6724690
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes0.005622
X-RAY DIFFRACTIONt_gen_planes0.013485
X-RAY DIFFRACTIONt_it1.287241820
X-RAY DIFFRACTIONt_nbd0.024845
LS refinement shellResolution: 2.4→2.54 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.2417 64 5.21 %
Rwork0.2253 1164 -
all0.2261 1228 -
obs--78.52 %

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