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- PDB-5eob: Crystal structure of CMET in complex with novel inhibitor -

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Basic information

Entry
Database: PDB / ID: 5eob
TitleCrystal structure of CMET in complex with novel inhibitor
ComponentsHepatocyte growth factor receptor
KeywordsTRANSFERASE / CMET inhibitor
Function / homology
Function and homology information


negative regulation of guanyl-nucleotide exchange factor activity / hepatocyte growth factor receptor 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-plexin signaling pathway involved in axon guidance / semaphorin receptor activity ...negative regulation of guanyl-nucleotide exchange factor activity / hepatocyte growth factor receptor 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-plexin signaling pathway involved in axon guidance / semaphorin receptor activity / MET receptor recycling / semaphorin receptor complex / 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 / 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 / neuron differentiation / Negative regulation of MET activity / receptor protein-tyrosine kinase / 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 / 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 / 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-5QQ / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.75 Å
AuthorsLiu, Q. / Chen, T. / Xu, Y.
Citation
Journal: Eur.J.Med.Chem. / Year: 2016
Title: Discovery of 6-(difluoro(6-(4-fluorophenyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)methyl)quinoline as a highly potent and selective c-Met inhibitor
Authors: Zhan, Z. / Peng, X. / Liu, Q. / Chen, F. / Ji, Y. / Yao, S. / Xi, Y. / Lin, Y. / Chen, T. / Xu, Y. / Ai, J. / Geng, M. / Duan, W.
#1: Journal: 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
DepositionNov 10, 2015Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Oct 19, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 20, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)36,4262
Polymers36,0341
Non-polymers3921
Water2,144119
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13850 Å2
Unit cell
Length a, b, c (Å)37.880, 43.390, 86.080
Angle α, β, γ (deg.)90.000, 92.680, 90.000
Int Tables number4
Space group name H-MP1211

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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: pET15b / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-5QQ / 6-[bis(fluoranyl)-[6-(4-fluorophenyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]methyl]quinoline


Mass: 392.337 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H11F3N6
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 119 / 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: 1.96 Å3/Da / Density % sol: 37.28 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 19-20%(w/v)PEG 3350, 200mM MgSO4, 100mM Tris-HCl

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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: Mar 22, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 1.75→23.92 Å / Num. obs: 51912 / % possible obs: 94.1 % / Observed criterion σ(I): -3 / Redundancy: 1.92 % / Biso Wilson estimate: 17.01 Å2 / Rmerge F obs: 0.996 / Rmerge(I) obs: 0.061 / Rrim(I) all: 0.085 / Χ2: 1.021 / Net I/σ(I): 11.04 / Num. measured all: 99851
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Highest resolution (Å)Rmerge F obsRmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible all
1.75-1.80.6780.3842.976775408538560.53894.4
1.8-1.840.7830.3333.877305392637650.46795.9
1.84-1.90.8140.2864.597349394737550.40295.1
1.9-1.960.8680.2225.516966369435620.31296.4
1.96-2.020.8920.1886.546899367035320.26496.2
2.02-2.090.9370.1457.796553351433530.20495.4
2.09-2.170.9640.1148.976336339832420.1695.4
2.17-2.260.970.09610.176069326431230.13595.7
2.26-2.360.980.08111.115910317130260.11495.4
2.36-2.470.9840.0712.195499296028200.09895.3
2.47-2.610.9870.06312.985378289227590.08995.4
2.61-2.770.990.05214.844952268525430.07394.7
2.77-2.960.9930.04516.294662253424050.06394.9
2.96-3.20.9940.03918.224320237322330.05494.1
3.2-3.50.9950.03519.773510216818590.04985.7
3.5-3.910.9950.03222.082999196616220.04582.5
3.91-4.520.9960.0323.482899171815610.04290.9
4.52-5.530.9960.02623.662570147213750.03793.4
5.53-7.830.9960.02524.212057112510640.03694.6
7.830.9980.02424.358436224570.03473.5

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation1.75 Å23.92 Å
Translation1.75 Å23.92 Å

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHASER2.3.0phasing
PHENIX(phenix.refine: 1.8.2_1309)refinement
PDB_EXTRACT3.15data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.75→23.915 Å / FOM work R set: 0.8903 / SU ML: 0.18 / Cross valid method: FREE R-VALUE / σ(F): 0.89 / Phase error: 18.52 / Stereochemistry target values: MLHL
RfactorNum. reflection% reflection
Rfree0.1974 1553 2.99 %
Rwork0.1729 50357 -
obs0.1736 51910 94.1 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 67.48 Å2 / Biso mean: 19.36 Å2 / Biso min: 5.48 Å2
Refinement stepCycle: final / Resolution: 1.75→23.915 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2257 0 29 119 2405
Biso mean--15.37 25.78 -
Num. residues----288
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072348
X-RAY DIFFRACTIONf_angle_d1.0833189
X-RAY DIFFRACTIONf_chiral_restr0.078356
X-RAY DIFFRACTIONf_plane_restr0.005399
X-RAY DIFFRACTIONf_dihedral_angle_d13.697849
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 (%)
1.7501-1.80650.26461410.23734573471494
1.8065-1.87110.23431440.20284646479096
1.8711-1.9460.20691440.19334668481296
1.946-2.03450.21861380.17734671480996
2.0345-2.14170.19131490.16534696484595
2.1417-2.27580.24061420.15924602474495
2.2758-2.45130.2181440.16374625476996
2.4513-2.69770.19831420.16264697483995
2.6977-3.08740.17931430.16084599474295
3.0874-3.8870.16841330.154196432986
3.887-23.91760.18291330.19074384451790

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