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- PDB-4gg5: Crystal structure of CMET in complex with novel inhibitor -

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Basic information

Entry
Database: PDB / ID: 4gg5
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-0J3 / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.423 Å
AuthorsLiu, Q.F. / Chen, T.T. / Xu, Y.C.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Multisubstituted quinoxalines and pyrido[2,3-d]pyrimidines: Synthesis and SAR study as tyrosine kinase c-Met inhibitors.
Authors: Wu, K. / Ai, J. / Liu, Q. / Chen, T. / Zhao, A. / Peng, X. / Wang, Y. / Ji, Y. / Yao, Q. / Xu, Y. / Geng, M. / Zhang, A.
History
DepositionAug 5, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 3, 2012Provider: repository / Type: Initial release
Revision 1.1Oct 17, 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)36,4792
Polymers36,0341
Non-polymers4451
Water95553
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)65.641, 65.641, 186.174
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: c-MET, MET / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-0J3 / 3-(4-methylpiperazin-1-yl)-N-(3-nitrobenzyl)-7-(trifluoromethyl)quinolin-5-amine


Mass: 445.438 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H22F3N5O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 53 / 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: 2.78 Å3/Da / Density % sol: 55.8 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1M HEPES, 8% isopropanol, 3mM TECP, 16% PEG4000, 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 15, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 2.42→62.058 Å / Num. all: 15939 / Num. obs: 15512 / % possible obs: 97.6 % / Observed criterion σ(I): -3 / Biso Wilson estimate: 48.234 Å2 / Rmerge(I) obs: 0.094 / Net I/σ(I): 15.73
Reflection shell

Diffraction-ID: 1

Resolution (Å)Highest resolution (Å)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. unique obs% possible all
2.42-2.480.6383.098778114798.8
2.48-2.550.5313.778860112598.2
2.55-2.620.4654.328713110998.2
2.62-2.710.3935.218520106199
2.71-2.790.3426.248226104098.5
2.79-2.890.2717.648284101798.9
2.89-30.2319.08821997798.1
3-3.120.17611.95784094998.8
3.12-3.260.15114.37780189199
3.26-3.420.11418.01760387697.9
3.42-3.610.09422.22705881497.6
3.61-3.830.08124.62667678598.2
3.83-4.090.06728.18618373296.7
4.09-4.420.0631.47564668195.6
4.42-4.840.05532.3538964397.1
4.84-5.410.05331.91476757496.3
5.41-6.250.05230.96434050895.3
6.25-7.650.04532.64371145095.1
7.65-10.820.03437.58287036194.5
10.820.0335.09138819985.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHASERphasing
PHENIX1.8_1069refinement
PDB_EXTRACT3.11data extraction
Blu-Icedata collection
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.423→37.968 Å / Occupancy max: 1 / Occupancy min: 0.1 / FOM work R set: 0.7953 / SU ML: 0.35 / σ(F): 1.34 / Phase error: 26.39 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2681 1545 10.01 %10.01%
Rwork0.2099 ---
obs0.2157 15442 94.99 %-
all-15939 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 104.49 Å2 / Biso mean: 37.1614 Å2 / Biso min: 14.44 Å2
Refinement stepCycle: LAST / Resolution: 2.423→37.968 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2172 0 32 53 2257
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082271
X-RAY DIFFRACTIONf_angle_d1.1693080
X-RAY DIFFRACTIONf_chiral_restr0.081340
X-RAY DIFFRACTIONf_plane_restr0.005382
X-RAY DIFFRACTIONf_dihedral_angle_d16.973839
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.423-2.50150.38831120.28511007111978
2.5015-2.59090.33161280.26331152128090
2.5909-2.69460.34341410.24831262140397
2.6946-2.81720.31051430.24311297144098
2.8172-2.96570.32261440.24171288143299
2.9657-3.15140.31061430.23151292143598
3.1514-3.39460.27331440.20991294143898
3.3946-3.73590.23351440.18181298144298
3.7359-4.27590.1841440.17411297144197
4.2759-5.38470.22611480.17661326147496
5.3847-37.97220.3171540.23171384153894

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