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- PDB-4dei: Crystal structure of c-Met in complex with triazolopyridinone inh... -

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Basic information

Entry
Database: PDB / ID: 4dei
TitleCrystal structure of c-Met in complex with triazolopyridinone inhibitor 24
ComponentsHepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / proto-oncogene / inhibitor / receptor tyrosine kinase / RTK / ATP-binding / hepatocyte growth factor/scatter factor / HGF/SF / phosphoprotein / 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 / endothelial cell morphogenesis / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET interacts with TNS proteins / MET Receptor Activation / semaphorin receptor activity / positive regulation of endothelial cell chemotaxis ...hepatocyte growth factor receptor activity / negative regulation of guanyl-nucleotide exchange factor activity / Drug-mediated inhibition of MET activation / endothelial cell morphogenesis / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET interacts with TNS proteins / MET Receptor Activation / semaphorin receptor activity / positive regulation of endothelial cell chemotaxis / 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 / 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 / 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 / liver development / molecular function activator activity / Negative regulation of MET activity / receptor protein-tyrosine kinase / neuron differentiation / cell surface receptor protein tyrosine kinase signaling pathway / 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 phosphatase binding / protein tyrosine kinase activity / cell surface receptor signaling pathway / receptor complex / phosphorylation / cell surface / signal transduction / positive regulation of transcription by RNA polymerase II / extracellular region / ATP binding / membrane / 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 / 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 / Immunoglobulin E-set / Tyrosine-protein kinase, catalytic domain / Tyrosine 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 / 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-0JL / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Difference Fourier / Resolution: 2.05 Å
AuthorsWhittington, D.A. / Long, A.M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Discovery and optimization of a potent and selective triazolopyridinone series of c-Met inhibitors.
Authors: Bode, C.M. / Boezio, A.A. / Albrecht, B.K. / Bellon, S.F. / Berry, L. / Broome, M.A. / Choquette, D. / Dussault, I. / Lewis, R.T. / Lin, M.H. / Rex, K. / Whittington, D.A. / Yang, Y. / Harmange, J.C.
History
DepositionJan 20, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 30, 2012Provider: repository / Type: Initial release
Revision 1.1Jun 20, 2012Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / 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

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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)35,6782
Polymers35,2161
Non-polymers4631
Water3,009167
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.788, 42.592, 158.200
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 / 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: 35215.715 Da / Num. of mol.: 1
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-0JL / 3-{(1S)-1-[3-(2-methoxyethoxy)quinolin-6-yl]ethyl}-5-(3-methyl-1,2-thiazol-5-yl)-3,5-dihydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one


Mass: 462.524 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H22N6O3S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 167 / 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 Å3/Da / Density % sol: 38.47 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.8
Details: 15% PEG 4000, 0.1 M HEPES, 6% isopropanol, 3% ethanol, 40 mM beta-mercaptoethanol, pH 7.8, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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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: Apr 3, 2010 / Details: varimax optics
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.05→50 Å / Num. all: 18565 / Num. obs: 14592 / % possible obs: 78.6 % / Observed criterion σ(I): -3 / Redundancy: 3.6 % / Biso Wilson estimate: 30.1 Å2 / Rmerge(I) obs: 0.08 / Χ2: 1.137 / Net I/σ(I): 10.7
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.05-2.1230.57881.153143.2
2.12-2.213.50.38910331.267156.8
2.21-2.313.70.35912251.22167.7
2.31-2.433.80.30813831.216176.5
2.43-2.583.70.23414971.163182.2
2.58-2.783.70.16815501.179183.7
2.78-3.063.70.11715671.135185.1
3.06-3.513.50.08417371.231192.8
3.51-4.423.70.05518440.924198.2
4.42-503.70.04119681.027196.7

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.1data extraction
CrystalCleardata collection
DENZOdata reduction
RefinementMethod to determine structure: Difference Fourier / Resolution: 2.05→39.56 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.905 / WRfactor Rfree: 0.2787 / WRfactor Rwork: 0.2128 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.7961 / SU B: 5.704 / SU ML: 0.16 / SU R Cruickshank DPI: 0.4002 / SU Rfree: 0.2768 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.4 / ESU R Free: 0.277 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS; U VALUES: REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2887 739 5.1 %RANDOM
Rwork0.2208 ---
obs0.2241 14549 78.66 %-
all-18496 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 71.73 Å2 / Biso mean: 39.1061 Å2 / Biso min: 17.85 Å2
Baniso -1Baniso -2Baniso -3
1--0.04 Å20 Å20 Å2
2--0.24 Å20 Å2
3----0.21 Å2
Refinement stepCycle: LAST / Resolution: 2.05→39.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2286 0 33 167 2486
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0222379
X-RAY DIFFRACTIONr_angle_refined_deg1.031.9823222
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9125284
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.30723.33399
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.68415411
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.0131513
X-RAY DIFFRACTIONr_chiral_restr0.0680.2356
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0211767
X-RAY DIFFRACTIONr_mcbond_it0.64221428
X-RAY DIFFRACTIONr_mcangle_it1.17532314
X-RAY DIFFRACTIONr_scbond_it0.9243951
X-RAY DIFFRACTIONr_scangle_it1.4474.5908
LS refinement shellResolution: 2.05→2.103 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.383 24 -
Rwork0.289 533 -
all-557 -
obs--41.54 %

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