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- PDB-5eyc: Crystal structure of c-Met in complex with naphthyridinone inhibitor 5 -

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Basic information

Entry
Database: PDB / ID: 5eyc
TitleCrystal structure of c-Met in complex with naphthyridinone inhibitor 5
ComponentsHepatocyte growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / phosphotransferase / inhibitor / cancer / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / liver development / basal plasma membrane / InlB-mediated entry of Listeria monocytogenes into host cell / excitatory postsynaptic potential / molecular function activator activity / receptor protein-tyrosine kinase / Negative regulation of MET activity / 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 / Tyrosine protein kinases specific active-site signature. / Immunoglobulin E-set / 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-5SZ / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsWhittington, D.A. / Long, A.M.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Discovery of (R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (AMG 337), a Potent and Selective ...Title: Discovery of (R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (AMG 337), a Potent and Selective Inhibitor of MET with High Unbound Target Coverage and Robust In Vivo Antitumor Activity.
Authors: Boezio, A.A. / Copeland, K.W. / Rex, K. / K Albrecht, B. / Bauer, D. / Bellon, S.F. / Boezio, C. / Broome, M.A. / Choquette, D. / Coxon, A. / Dussault, I. / Hirai, S. / Lewis, R. / Lin, M.H. ...Authors: Boezio, A.A. / Copeland, K.W. / Rex, K. / K Albrecht, B. / Bauer, D. / Bellon, S.F. / Boezio, C. / Broome, M.A. / Choquette, D. / Coxon, A. / Dussault, I. / Hirai, S. / Lewis, R. / Lin, M.H. / Lohman, J. / Liu, J. / Peterson, E.A. / Potashman, M. / Shimanovich, R. / Teffera, Y. / Whittington, D.A. / Vaida, K.R. / Harmange, J.C.
History
DepositionNov 24, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 10, 2016Provider: repository / Type: Initial release
Revision 1.1Feb 17, 2016Group: Database references
Revision 1.2Apr 6, 2016Group: Database references
Revision 1.3Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)35,6062
Polymers35,2161
Non-polymers3901
Water4,594255
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.073, 43.267, 158.020
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: 35215.715 Da / Num. of mol.: 1 / Fragment: residues 1048-1351
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-5SZ / 6-[(1~{R})-1-[8-fluoranyl-6-(3-methyl-1,2-oxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl]ethyl]-1,6-naphthyridin-5-one


Mass: 390.371 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H15FN6O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 255 / 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: 2.04 Å3/Da / Density % sol: 39.77 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.8
Details: 12% PEG 4000, 3% (v/v) ethanol, 6% (v/v) isopropanol, 40 mM beta-mercaptoethanol, 100 mM HEPES (pH 7.8)

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jun 7, 2011 / Details: Varimax HR
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. obs: 22824 / % possible obs: 82.4 % / Observed criterion σ(I): -3 / Redundancy: 2.9 % / Biso Wilson estimate: 28.99 Å2 / Rmerge(I) obs: 0.034 / Χ2: 1.083 / Net I/av σ(I): 20.341 / Net I/σ(I): 24.5 / Num. measured all: 65999
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allΧ2% possible all
1.8-1.862.20.3253.68610211.67137.7
1.86-1.942.60.27317111.69663.3
1.94-2.032.90.21723601.52686.6
2.03-2.1330.15923951.40688.4
2.13-2.272.90.1123741.24586.4
2.27-2.442.70.07823291.11284.5
2.44-2.692.50.05324250.91988
2.69-3.082.40.03626480.75395.1
3.08-3.883.10.02827480.56797.4
3.88-503.80.02328130.84293.8

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMAC5.6.0117refinement
PDB_EXTRACT3.15data extraction
CrystalCleardata collection
HKL-2000data reduction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4XMO

4xmo


Resolution: 1.8→41.74 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.937 / WRfactor Rfree: 0.267 / WRfactor Rwork: 0.2014 / FOM work R set: 0.8195 / SU B: 3.44 / SU ML: 0.106 / SU R Cruickshank DPI: 0.1796 / SU Rfree: 0.1671 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.18 / ESU R Free: 0.167 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2472 1183 5.2 %RANDOM
Rwork0.1917 ---
obs0.1946 21619 82.48 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 113.16 Å2 / Biso mean: 31.058 Å2 / Biso min: 15.39 Å2
Baniso -1Baniso -2Baniso -3
1--0.51 Å20 Å20 Å2
2--1.91 Å20 Å2
3----1.39 Å2
Refinement stepCycle: final / Resolution: 1.8→41.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2297 0 29 255 2581
Biso mean--27.5 41.05 -
Num. residues----288
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.022396
X-RAY DIFFRACTIONr_bond_other_d0.0010.021636
X-RAY DIFFRACTIONr_angle_refined_deg1.1561.9793250
X-RAY DIFFRACTIONr_angle_other_deg0.8553.0013977
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.185288
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.9623.2100
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.99715417
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.0691514
X-RAY DIFFRACTIONr_chiral_restr0.0660.2361
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212600
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02489
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.448 38 -
Rwork0.373 637 -
all-675 -
obs--34.21 %

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