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- PDB-4mxc: Crystal structure of CMET in complex with novel inhibitor -

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Basic information

Entry
Database: PDB / ID: 4mxc
TitleCrystal structure of CMET in complex with novel inhibitor
ComponentsHepatocyte growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / CMET inhibitor / 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-DWF / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.632 Å
AuthorsLiu, Q.F. / Chen, T.T. / Xu, Y.C.
CitationJournal: ACS MED.CHEM.LETT. / Year: 2014
Title: Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity
Authors: Zhan, Z.S. / Ai, J. / Liu, Q.F. / Ji, Y.C. / Chen, T.T. / Xu, Y.C. / Geng, M.Y. / Duan, W.H.
History
DepositionSep 26, 2013Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Oct 15, 2014Provider: repository / Type: Initial release
Revision 1.1Apr 22, 2015Group: Database references
Revision 1.2Mar 20, 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)36,6272
Polymers36,0341
Non-polymers5941
Water3,675204
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.963, 80.935, 90.867
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 / 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: Protein Kinase domain, UNP resodies 1038-1346
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CMET, MET / Plasmid: pET15b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-DWF / N-(3-fluoro-4-{[2-({3-[(methylsulfonyl)methyl]phenyl}amino)pyrimidin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide


Mass: 593.601 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H25F2N5O5S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 204 / 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: 2.19 Å3/Da / Density % sol: 43.89 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 19-20%(w/v)PEG 3350, 200mM MgSO4, 100mM Tris-HCl, pH 7.5, vapor diffusion, hanging drop, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.9791 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Feb 17, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 1.63→50 Å / Num. obs: 39557 / % possible obs: 98.3 % / Redundancy: 6 % / Biso Wilson estimate: 13.95 Å2
Reflection shellResolution: 1.63→1.66 Å / Redundancy: 5.7 % / % possible all: 96.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHASERphasing
PHENIX1.8.2_1309refinement
PDB_EXTRACT3.11data extraction
Blu-Icedata collection
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.632→36.967 Å / Occupancy max: 1 / Occupancy min: 0 / SU ML: 0.11 / σ(F): 1.34 / Phase error: 19.13 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2075 1982 5.03 %
Rwork0.1791 --
obs0.1805 39420 98.05 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 18.589 Å2
Refinement stepCycle: LAST / Resolution: 1.632→36.967 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2306 0 42 204 2552
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072432
X-RAY DIFFRACTIONf_angle_d1.1623307
X-RAY DIFFRACTIONf_dihedral_angle_d12.831902
X-RAY DIFFRACTIONf_chiral_restr0.076366
X-RAY DIFFRACTIONf_plane_restr0.005415
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.6321-1.67290.21581300.192259196
1.6729-1.71810.23481330.1913264098
1.7181-1.76870.20751560.1871262699
1.7687-1.82580.2441340.1886263898
1.8258-1.8910.22181500.1751263499
1.891-1.96670.23311240.1758272399
1.9667-2.05620.21081450.1744266199
2.0562-2.16460.20441400.1658269499
2.1646-2.30020.18141510.1674267699
2.3002-2.47780.20591430.1714269499
2.4778-2.72710.22471470.1826268899
2.7271-3.12150.20991450.1814270298
3.1215-3.9320.18431390.1749272798
3.932-36.97670.20831450.1878274494

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