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- PDB-5ya5: CRYSTAL STRUCTURE OF c-MET IN COMPLEX WITH NOVEL INHIBITOR -

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Basic information

Entry
Database: PDB / ID: 5ya5
TitleCRYSTAL STRUCTURE OF c-MET IN COMPLEX WITH NOVEL INHIBITOR
ComponentsHepatocyte growth factor receptor
KeywordsTRANSFERASE/INHIBITOR / c-MET inhibitor / 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 / 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 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-6TD / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.89 Å
AuthorsLiu, Q. / Xu, Y.
CitationJournal: Eur J Med Chem / Year: 2018
Title: Discovery, optimization and biological evaluation for novel c-Met kinase inhibitors
Authors: Yuan, H. / Liu, Q. / Zhang, L. / Hu, S. / Chen, T. / Li, H. / Chen, Y. / Xu, Y. / Lu, T.
History
DepositionAug 30, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 4, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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)36,3952
Polymers36,0341
Non-polymers3611
Water1,946108
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13310 Å2
Unit cell
Length a, b, c (Å)42.360, 47.340, 158.690
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: 36033.594 Da / Num. of mol.: 1 / Fragment: UNP residues 1038-1346
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-6TD / 2-[3-(4-methoxybenzyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl]-1H-indole / 6-(1H-indol-2-yl)-3-(4-methoxybenzyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole


Mass: 361.420 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H15N5OS / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 108 / 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: 2.21 Å3/Da / Density % sol: 44.29 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1M Tris pH7.5, 15% glycerol, 12% MPD, 5% isopropanol, 15% PEG5Kmme

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.9791 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 15, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 1.89→40.927 Å / Num. obs: 49233 / % possible obs: 99.7 % / Observed criterion σ(I): -3 / Redundancy: 3.802 % / Biso Wilson estimate: 28.59 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.046 / Rrim(I) all: 0.053 / Χ2: 0.974 / Net I/σ(I): 17.33 / Num. measured all: 187189 / Scaling rejects: 16
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
1.89-1.943.8150.3883.4936570.8620.453100
1.94-1.993.8090.3224.2435730.8910.37599.9
1.99-2.053.8170.2365.7534660.9380.27599.8
2.05-2.113.8260.1857.1833710.9610.21599.9
2.11-2.183.8220.1468.6532180.9770.17199.9
2.18-2.263.8180.11510.9632110.9850.13499.9
2.26-2.343.8210.09612.7730280.9890.112100
2.34-2.443.8280.08314.4828880.9910.09799.9
2.44-2.553.8250.07116.6228220.9930.08299.8
2.55-2.673.8110.0562026690.9960.065100
2.67-2.823.8140.04822.8225480.9960.056100
2.82-2.993.8180.04225.2224070.9970.04999.9
2.99-3.193.7880.03828.5822570.9970.04599.9
3.19-3.453.7790.03531.8521190.9980.04100
3.45-3.783.7570.03434.119220.9970.0499.9
3.78-4.233.7370.03135.8717840.9980.036100
4.23-4.883.6780.03236.0315250.9980.03799.7
4.88-5.983.8740.03136.7213070.9980.03699.9
5.98-8.453.8020.02837.199930.9980.03298.8
8.45-40.9273.3140.02635.514680.9980.03184.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHASERphasing
PHENIX(phenix.refine: 1.8_1069)refinement
PDB_EXTRACT3.22data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4GG5

4gg5


Resolution: 1.89→40.927 Å / SU ML: 0.19 / Cross valid method: FREE R-VALUE / σ(F): 1.26 / Phase error: 22.99
RfactorNum. reflection% reflection
Rfree0.2349 1464 2.97 %
Rwork0.2114 --
obs0.2121 49227 99.71 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 82.15 Å2 / Biso mean: 38.1 Å2 / Biso min: 15.49 Å2
Refinement stepCycle: final / Resolution: 1.89→40.927 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2152 0 26 108 2286
Biso mean--40.2 34.45 -
Num. residues----273
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072240
X-RAY DIFFRACTIONf_angle_d1.0953041
X-RAY DIFFRACTIONf_chiral_restr0.081340
X-RAY DIFFRACTIONf_plane_restr0.005378
X-RAY DIFFRACTIONf_dihedral_angle_d16.034810
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.89-1.95760.25611460.231948004946100
1.9576-2.0360.23811450.22647964941100
2.036-2.12860.24781450.214747764921100
2.1286-2.24080.25451460.211847964942100
2.2408-2.38120.27321470.219147694916100
2.3812-2.56510.26641490.223847604909100
2.5651-2.82310.26461470.223348074954100
2.8231-3.23150.26261490.221847984947100
3.2315-4.07080.19591470.194847584905100
4.0708-40.93650.20721430.2044703484698

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