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

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Basic information

Entry
Database: PDB / ID: 5uab
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 / negative regulation of guanyl-nucleotide exchange factor 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 receptor activity / positive regulation of endothelial cell chemotaxis ...hepatocyte growth factor receptor activity / negative regulation of guanyl-nucleotide exchange factor 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 receptor activity / positive regulation of endothelial cell chemotaxis / 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 / 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 / basal plasma membrane / negative regulation of autophagy / InlB-mediated entry of Listeria monocytogenes into host cell / liver development / molecular function activator activity / Negative regulation of MET activity / receptor protein-tyrosine kinase / neuron differentiation / cell surface receptor protein tyrosine kinase signaling pathway / 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 / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-84M / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 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
Revision 1.3Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,0574
Polymers38,5791
Non-polymers4793
Water2,846158
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area370 Å2
ΔGint-13 kcal/mol
Surface area13960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.333, 47.167, 159.821
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 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf9
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-84M / N-{6-[([1,2,4]triazolo[4,3-a]pyridin-3-yl)sulfanyl]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide


Mass: 351.386 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H13N7OS
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-CL / CHLORIDE ION / Chloride


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


Mass: 18.015 Da / Num. of mol.: 158 / 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: 2.07 Å3/Da / Density % sol: 40.52 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.8
Details: 16.% PEG MME 5000, 15.% Isopropanol, 0.1M HEPES pH 7.8
PH range: 6.9-7.8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.9764848 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: May 29, 2008 / Details: Mirror: Rh coated flat, toroidal focusing
RadiationMonochromator: Si(111) and Si(220) double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9764848 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 24319 / % possible obs: 92.8 % / Redundancy: 6.3 % / Rmerge(I) obs: 0.093 / Χ2: 1.007 / Net I/σ(I): 11.1 / Num. measured all: 154062
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.9-1.962.90.28213970.927165.9
1.96-2.0240.26617050.921179
2.02-2.095.20.23518671.006188.3
2.09-2.175.90.22220500.947195.3
2.17-2.276.40.18420961.012197.5
2.27-2.396.90.16321130.918197.8
2.39-2.547.20.14121010.9197.2
2.54-2.747.20.10921101.054197.6
2.74-3.027.20.08321541.078197.5
3.02-3.457.10.06521491.079198.3
3.45-4.357.20.0722201.163199.2
4.35-506.90.09923570.933199

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
PDB_EXTRACT3.22data extraction
HKL-2000data scaling
HKL-2000data reduction
PHASERphasing
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→25 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.931 / SU B: 7.364 / SU ML: 0.109 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.168 / ESU R Free: 0.149 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2291 1162 4.8 %RANDOM
Rwork0.1949 ---
obs0.1966 23091 92.74 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 113.21 Å2 / Biso mean: 45.467 Å2 / Biso min: 21 Å2
Baniso -1Baniso -2Baniso -3
1--1.91 Å20 Å2-0 Å2
2---1.93 Å20 Å2
3---3.84 Å2
Refinement stepCycle: final / Resolution: 1.9→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2302 0 32 158 2492
Biso mean--42.97 41.96 -
Num. residues----288
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0192399
X-RAY DIFFRACTIONr_bond_other_d0.0020.022299
X-RAY DIFFRACTIONr_angle_refined_deg1.1371.9693252
X-RAY DIFFRACTIONr_angle_other_deg0.87535289
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2555285
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.56723.4100
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.16615405
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.7731511
X-RAY DIFFRACTIONr_chiral_restr0.0640.2361
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212663
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02552
LS refinement shellResolution: 1.899→1.948 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.298 66 -
Rwork0.294 1153 -
all-1219 -
obs--64.6 %
Refinement TLS params.Method: refined / Origin x: -9.9642 Å / Origin y: 0.5036 Å / Origin z: 15.9769 Å
111213212223313233
T0.1267 Å2-0.0258 Å2-0.0038 Å2-0.0934 Å2-0.0247 Å2--0.0123 Å2
L1.9782 °20.4777 °20.3172 °2-2.5735 °2-0.3194 °2--1.9836 °2
S0.0792 Å °-0.4211 Å °0.1295 Å °0.5207 Å °-0.1195 Å °-0.0152 Å °-0.2618 Å °-0.0011 Å °0.0403 Å °

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