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- PDB-5uad: MET Tyrosine Kinase Inhibition Enhances the Antitumor Efficacy of... -

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Basic information

Entry
Database: PDB / ID: 5uad
TitleMET Tyrosine Kinase Inhibition Enhances the Antitumor Efficacy of an HGF Antibody
ComponentsHepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE/INHIBITOR / MET / Tyrosine Kinase / Inhibitor / Antitumor / 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 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-84P / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsHoffman, I.D. / Lawson, J.D.
CitationJournal: Mol. Cancer Ther. / Year: 2017
Title: MET Tyrosine Kinase Inhibition Enhances the Antitumor Efficacy of an HGF Antibody.
Authors: Farrell, P.J. / Matuszkiewicz, J. / Balakrishna, D. / Pandya, S. / Hixon, M.S. / Kamran, R. / Chu, S. / Lawson, J.D. / Okada, K. / Hori, A. / Mizutani, A. / Iwata, H. / de Jong, R. / Hibner, B. / Vincent, P.
History
DepositionDec 19, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 31, 2017Provider: repository / Type: Initial release
Revision 1.1Jul 19, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software

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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)39,0273
Polymers38,5791
Non-polymers4492
Water2,090116
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area130 Å2
ΔGint-12 kcal/mol
Surface area14300 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.612, 47.468, 161.142
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: 38578.504 Da / Num. of mol.: 1 / Fragment: UNP residues 1041-1378
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-84P / N-(6-{[6-(1-methyl-1H-pyrazol-4-yl)-1H-benzotriazol-1-yl]methyl}imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide


Mass: 413.435 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H19N9O
#3: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 116 / 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: 2.11 Å3/Da / Density % sol: 44.77 %
Crystal growTemperature: 273 K / Method: vapor diffusion, sitting drop / pH: 7.2 / Details: 19.% PEG 3350, 12.% Isopropanol, 0.1M HEPES pH 7.2 / PH range: 6.9-7.8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.9764848 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Feb 20, 2009
RadiationMonochromator: Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9764848 Å / Relative weight: 1
ReflectionResolution: 2.25→50 Å / Num. obs: 15939 / % possible obs: 98 % / Redundancy: 4.4 % / Rmerge(I) obs: 0.096 / Χ2: 1.004 / Net I/σ(I): 7.7 / Num. measured all: 70139
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.25-2.293.60.5246841.061187.4
2.29-2.333.80.5047150.974191.9
2.33-2.384.10.4287980.981195.7
2.38-2.424.10.4447390.994197
2.42-2.484.40.4278030.977198.6
2.48-2.534.50.4127770.992199.4
2.53-2.64.50.3487960.944199.6
2.6-2.674.60.2818231.061199.9
2.67-2.754.50.2757670.986199.7
2.75-2.834.50.2328101.0391100
2.83-2.944.50.2037951.0041100
2.94-3.054.60.168161.012199.5
3.05-3.194.50.1378021.025199.8
3.19-3.364.50.1138101.036199.6
3.36-3.574.50.0828070.98199.6
3.57-3.854.60.0788101.018199.4
3.85-4.234.50.0668271.015199
4.23-4.854.50.068191.027199.4
4.85-6.14.50.0478430.968198.1
6.1-504.40.0398980.989197

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
HKL-2000data scaling
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
PHASERphasing
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.25→25 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.926 / WRfactor Rfree: 0.2388 / WRfactor Rwork: 0.1859 / FOM work R set: 0.8189 / SU B: 14.301 / SU ML: 0.179 / SU R Cruickshank DPI: 0.3102 / SU Rfree: 0.2343 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.31 / ESU R Free: 0.234 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2517 779 4.9 %RANDOM
Rwork0.1961 ---
obs0.1987 15118 97.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 133.17 Å2 / Biso mean: 49.075 Å2 / Biso min: 22.22 Å2
Baniso -1Baniso -2Baniso -3
1--1.37 Å2-0 Å2-0 Å2
2--0.39 Å2-0 Å2
3---0.98 Å2
Refinement stepCycle: final / Resolution: 2.25→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2321 0 32 116 2469
Biso mean--39.84 39.62 -
Num. residues----291
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0192416
X-RAY DIFFRACTIONr_bond_other_d0.0020.022299
X-RAY DIFFRACTIONr_angle_refined_deg1.1751.973277
X-RAY DIFFRACTIONr_angle_other_deg0.88135289
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.55286
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.99223.529102
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.59715405
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.5711511
X-RAY DIFFRACTIONr_chiral_restr0.0650.2362
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212697
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02554
LS refinement shellResolution: 2.249→2.307 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.312 58 -
Rwork0.256 915 -
all-973 -
obs--85.2 %
Refinement TLS params.Method: refined / Origin x: 9.6201 Å / Origin y: -0.4469 Å / Origin z: 16.2402 Å
111213212223313233
T0.1558 Å2-0.023 Å2-0.0055 Å2-0.0941 Å20.0158 Å2--0.0154 Å2
L2.3809 °20.9096 °2-0.6535 °2-2.7879 °2-0.0865 °2--2.3171 °2
S0.1134 Å °-0.4534 Å °-0.113 Å °0.5541 Å °-0.1457 Å °-0.0092 Å °0.2882 Å °0.0391 Å °0.0323 Å °

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