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- PDB-4xyf: Crystal structure of c-Met in complex with (S)-5-(8-fluoro-3-(1-(... -

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Basic information

Entry
Database: PDB / ID: 4xyf
TitleCrystal structure of c-Met in complex with (S)-5-(8-fluoro-3-(1-(3-(2-methoxyethoxy)quinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-methylisoxazole
ComponentsHepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE/TRANSFERASE Inhibitor / receptor tyrosine kinase / inhibitor / complex / intracellular catalytic domain / TRANSFERASE-TRANSFERASE Inhibitor complex
Function / homology
Function and homology information


hepatocyte growth factor receptor activity / Drug-mediated inhibition of MET activation / MET activates STAT3 / endothelial cell morphogenesis / negative regulation of hydrogen peroxide-mediated programmed cell death / negative regulation of guanyl-nucleotide exchange factor activity / MET interacts with TNS proteins / MET Receptor Activation / positive regulation of endothelial cell chemotaxis / semaphorin receptor activity ...hepatocyte growth factor receptor activity / Drug-mediated inhibition of MET activation / MET activates STAT3 / endothelial cell morphogenesis / negative regulation of hydrogen peroxide-mediated programmed cell death / negative regulation of guanyl-nucleotide exchange factor activity / MET interacts with TNS proteins / MET Receptor Activation / positive regulation of endothelial cell chemotaxis / semaphorin receptor activity / MET receptor recycling / Sema4D mediated inhibition of cell attachment and migration / MET activates PTPN11 / pancreas development / MET activates RAP1 and RAC1 / MET activates PI3K/AKT signaling / negative regulation of Rho protein signal transduction / negative regulation of stress fiber assembly / semaphorin-plexin signaling pathway / MET activates PTK2 signaling / negative regulation of thrombin-activated receptor signaling pathway / branching morphogenesis of an epithelial tube / positive chemotaxis / establishment of skin barrier / MET activates RAS signaling / MECP2 regulates neuronal receptors and channels / phagocytosis / 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 / transmembrane receptor protein tyrosine kinase activity / positive regulation of kinase activity / Constitutive Signaling by Aberrant PI3K in Cancer / PIP3 activates AKT signaling / nervous system development / transmembrane receptor protein tyrosine kinase signaling pathway / cell migration / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein phosphatase binding / protein tyrosine kinase activity / positive regulation of protein kinase B signaling / cell surface receptor signaling pathway / receptor complex / 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 / WD40/YVTN repeat-like-containing domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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-44X / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsWhittington, D.A. / Long, A.M.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Discovery of Potent and Selective 8-Fluorotriazolopyridine c-Met Inhibitors.
Authors: Peterson, E.A. / Teffera, Y. / Albrecht, B.K. / Bauer, D. / Bellon, S.F. / Boezio, A. / Boezio, C. / Broome, M.A. / Choquette, D. / Copeland, K.W. / Dussault, I. / Lewis, R. / Lin, M.H. / ...Authors: Peterson, E.A. / Teffera, Y. / Albrecht, B.K. / Bauer, D. / Bellon, S.F. / Boezio, A. / Boezio, C. / Broome, M.A. / Choquette, D. / Copeland, K.W. / Dussault, I. / Lewis, R. / Lin, M.H. / Lohman, J. / Liu, J. / Potashman, M. / Rex, K. / Shimanovich, R. / Whittington, D.A. / Vaida, K.R. / Harmange, J.C.
History
DepositionFeb 2, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 11, 2015Provider: repository / Type: Initial release
Revision 1.1Mar 25, 2015Group: Database references

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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)35,6632
Polymers35,2161
Non-polymers4471
Water4,594255
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.893, 43.406, 157.978
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 / Fragment: kinase domain (UNP residues 1048-1351)
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-44X / 6-{(1S)-1-[8-fluoro-6-(3-methyl-1,2-oxazol-5-yl)[1,2,4]triazolo[4,3-a]pyridin-3-yl]ethyl}-3-(2-methoxyethoxy)quinoline


Mass: 447.462 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H22FN5O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 255 / 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: 2.04 Å3/Da / Density % sol: 39.69 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.8
Details: 13% PEG 4000, 100 mM HEPES, 6% (v/v) isopropanol, 3% (v/v) ethanol, 40 mM beta-mercaptoethanol

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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: Mar 26, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.85→50 Å / Num. all: 25556 / Num. obs: 20982 / % possible obs: 82.1 % / Observed criterion σ(I): -3 / Redundancy: 3.9 % / Biso Wilson estimate: 25.8 Å2 / Rmerge(I) obs: 0.054 / Χ2: 1.096 / Net I/av σ(I): 22.197 / Net I/σ(I): 19.6 / Num. measured all: 81489
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allΧ2% possible all
1.85-1.922.30.273.310031.25540.2
1.92-1.992.90.21415661.15662.3
1.99-2.0840.17219261.10676.6
2.08-2.194.20.13620521.04681.9
2.19-2.3340.10821291.07984.6
2.33-2.5140.08922541.0289
2.51-2.7640.06923711.00993.2
2.76-3.1640.05525070.9597.6
3.16-3.994.10.04725380.98798
3.99-504.20.0426361.45695.2

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Processing

Software
NameVersionClassification
CrystalCleardata collection
DENZOdata reduction
SCALEPACK1.98.5data scaling
PDB_EXTRACT3.15data extraction
EPMRphasing
REFMACrefinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4XMO
Resolution: 1.85→40 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.935 / WRfactor Rfree: 0.2459 / WRfactor Rwork: 0.1939 / FOM work R set: 0.8369 / SU B: 3.331 / SU ML: 0.102 / SU R Cruickshank DPI: 0.1966 / SU Rfree: 0.172 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.197 / ESU R Free: 0.172 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2359 1063 5.1 %RANDOM
Rwork0.1858 19873 --
obs0.1884 19873 82.14 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 102.37 Å2 / Biso mean: 29 Å2 / Biso min: 13.44 Å2
Baniso -1Baniso -2Baniso -3
1--0.77 Å20 Å20 Å2
2--1.46 Å20 Å2
3----0.69 Å2
Refinement stepCycle: final / Resolution: 1.85→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2311 0 33 255 2599
Biso mean--28.45 38.12 -
Num. residues----290
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.022423
X-RAY DIFFRACTIONr_bond_other_d0.0010.021655
X-RAY DIFFRACTIONr_angle_refined_deg1.2191.983288
X-RAY DIFFRACTIONr_angle_other_deg0.8673.0014020
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.495294
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.14723.168101
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.99615420
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.2641514
X-RAY DIFFRACTIONr_chiral_restr0.0720.2364
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212634
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02495
LS refinement shellResolution: 1.85→1.898 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.43 33 -
Rwork0.333 630 -
all-663 -
obs--36.25 %

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