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- PDB-3f66: Human c-Met Kinase in complex with quinoxaline inhibitor -

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Basic information

Entry
Database: PDB / ID: 3f66
TitleHuman c-Met Kinase in complex with quinoxaline inhibitor
ComponentsHepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE / c-Met / protein kinase / quinoxaline / Alternative splicing / ATP-binding / Chromosomal rearrangement / Disease mutation / Glycoprotein / Kinase / Membrane / Nucleotide-binding / Phosphoprotein / Polymorphism / Proto-oncogene / Receptor / Repeat / Signal / 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 / 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 / basal plasma membrane / negative regulation of autophagy / 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
GAMMA-BUTYROLACTONE / Chem-IHX / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsMeier, C. / Ceska, T.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Discovery of a novel series of quinoxalines as inhibitors of c-Met kinase.
Authors: Porter, J. / Lumb, S. / Lecomte, F. / Reuberson, J. / Foley, A. / Calmiano, M. / le Riche, K. / Edwards, H. / Delgado, J. / Franklin, R.J. / Gascon-Simorte, J.M. / Maloney, A. / Meier, C. / Batchelor, M.
History
DepositionNov 5, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 23, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Dec 27, 2023Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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
B: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,92110
Polymers67,6902
Non-polymers1,2308
Water8,161453
1
A: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4925
Polymers33,8451
Non-polymers6474
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4295
Polymers33,8451
Non-polymers5844
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.377, 47.587, 75.600
Angle α, β, γ (deg.)100.70, 103.62, 98.29
Int Tables number1
Space group name H-MP1

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Components

#1: Protein Hepatocyte growth factor receptor / C-Met / 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: 33845.242 Da / Num. of mol.: 2 / Fragment: UNP residues 1052-1349
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-IHX / 3-[3-(4-methylpiperazin-1-yl)-7-(trifluoromethyl)quinoxalin-5-yl]phenol


Mass: 388.386 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H19F3N4O
#3: Chemical
ChemComp-GBL / GAMMA-BUTYROLACTONE / DIHYDROFURAN-2(3H)-ONE / Gamma-Butyrolactone


Mass: 86.089 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C4H6O2
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 453 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsVAL TO LEU CONFLICT IN UNP DATABASE ENTRY P08581

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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: 2.36 Å3/Da / Density % sol: 47.83 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Nov 1, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.4→24.56 Å / Num. obs: 107820 / % possible obs: 88.5 % / Rmerge(I) obs: 0.051 / Rsym value: 0.036 / Net I/σ(I): 10.59
Reflection shellResolution: 1.4→1.47 Å / Rmerge(I) obs: 0.516 / Mean I/σ(I) obs: 2.01 / Num. unique all: 10482 / Rsym value: 0.365 / % possible all: 67

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.4→20 Å / Cor.coef. Fo:Fc: 0.974 / Cor.coef. Fo:Fc free: 0.958 / SU B: 4.143 / SU ML: 0.066 / ESU R: 0.071 / ESU R Free: 0.071 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.22491 3235 3 %RANDOM
Rwork0.16816 ---
obs-104583 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 24.32 Å2
Refinement stepCycle: LAST / Resolution: 1.4→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4620 0 87 453 5160
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0224833
X-RAY DIFFRACTIONr_bond_other_d0.0010.024423
X-RAY DIFFRACTIONr_angle_refined_deg1.6821.9816569
X-RAY DIFFRACTIONr_angle_other_deg1.267310293
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9815587
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.26622.935201
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.40915828
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.4461529
X-RAY DIFFRACTIONr_chiral_restr0.0980.2717
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.025319
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021014
X-RAY DIFFRACTIONr_nbd_refined0.220.21026
X-RAY DIFFRACTIONr_nbd_other0.2050.24433
X-RAY DIFFRACTIONr_nbtor_refined0.1870.22355
X-RAY DIFFRACTIONr_nbtor_other0.0830.22572
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1790.2350
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.3460.22
X-RAY DIFFRACTIONr_metal_ion_refined0.2290.21
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1870.217
X-RAY DIFFRACTIONr_symmetry_vdw_other0.3130.262
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1930.222
X-RAY DIFFRACTIONr_mcbond_it4.88822907
X-RAY DIFFRACTIONr_mcbond_other3.06421171
X-RAY DIFFRACTIONr_mcangle_it6.14234732
X-RAY DIFFRACTIONr_scbond_it8.12541990
X-RAY DIFFRACTIONr_scangle_it10.09661837
LS refinement shellHighest resolution: 1.4 Å / Num. reflection Rwork: 5217 / Total num. of bins used: 20

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