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- PDB-6ubw: MET Tyrosine Kinase Inhibition Enhances the Antitumor Efficacy of... -

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Basic information

Entry
Database: PDB / ID: 6ubw
TitleMET Tyrosine Kinase Inhibition Enhances the Antitumor Efficacy of an HGF Antibody
ComponentsHepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE-TRANSFERASE INHIBITOR / MET / Tyrosine Kinase / Inhibitor / Antitumor / 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 / 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 / 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
Similarity search - Domain/homology
Chem-84S / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 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
DepositionSep 13, 2019Deposition site: RCSB / Processing site: RCSB
SupersessionFeb 12, 2020ID: 5UAF
Revision 1.0Feb 12, 2020Provider: repository / Type: Initial release
Revision 1.1Aug 25, 2021Group: Database references / Category: citation / database_2
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)39,0633
Polymers38,5791
Non-polymers4852
Water2,990166
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area130 Å2
ΔGint-12 kcal/mol
Surface area14710 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.414, 47.398, 160.607
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 1023-1360
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Plasmid: pFastBac1-HM / Production host: Baculovirus expression vector pFastBac1-HM
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-84S / N-(6-{difluoro[6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide


Mass: 449.416 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H17F2N9O / Feature type: SUBJECT OF INVESTIGATION
#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.: 166 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.09 Å3/Da / Density % sol: 41.21 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 12% isopropanol, 10% PEG5000 MME, 0.06 M HEPES sodium, 0.04 M HEPES

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.9765 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: 0.9765 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 22773 / % possible obs: 99.5 % / Redundancy: 5.4 % / Rmerge(I) obs: 0.103 / Χ2: 1.016 / Net I/σ(I): 8.4 / Num. measured all: 123681
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2-2.034.40.62210700.946195.5
2.03-2.074.70.52910970.973198
2.07-2.1150.54110900.995199.2
2.11-2.155.20.51111331.023199.7
2.15-2.25.40.4111050.985199.7
2.2-2.255.60.38411361.035199.8
2.25-2.315.60.36411141.109199.8
2.31-2.375.60.29711381.0141100
2.37-2.445.80.27811171.0131100
2.44-2.525.60.26111381.059199.8
2.52-2.615.60.22311051.031199.9
2.61-2.715.60.17611421.011199.9
2.71-2.845.60.15411461.02199.7
2.84-2.995.60.12911351.018199.7
2.99-3.175.50.11111491.024199.9
3.17-3.425.40.09411461.024199.8
3.42-3.765.30.08111651.014199.8
3.76-4.315.40.06611681.001199.8
4.31-5.435.70.05111880.9921100
5.43-505.80.04212911199.9

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMAC5.8.0135refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→25 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.932 / SU B: 8.885 / SU ML: 0.123 / SU R Cruickshank DPI: 0.181 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.181 / ESU R Free: 0.158
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2246 1127 5 %RANDOM
Rwork0.1868 ---
obs0.1887 21568 99.18 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 115.48 Å2 / Biso mean: 42.276 Å2 / Biso min: 17.95 Å2
Baniso -1Baniso -2Baniso -3
1--2.11 Å2-0 Å2-0 Å2
2---0.5 Å20 Å2
3---2.61 Å2
Refinement stepCycle: final / Resolution: 2→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2364 0 34 166 2564
Biso mean--33.7 41.15 -
Num. residues----296
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0192461
X-RAY DIFFRACTIONr_bond_other_d0.0020.022360
X-RAY DIFFRACTIONr_angle_refined_deg1.1471.9763337
X-RAY DIFFRACTIONr_angle_other_deg0.88135433
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2685291
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.94323.529102
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.81515421
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.6741511
X-RAY DIFFRACTIONr_chiral_restr0.0660.2368
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212736
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02559
LS refinement shellResolution: 2→2.047 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.332 74 -
Rwork0.254 1459 -
obs--93.08 %
Refinement TLS params.Method: refined / Origin x: 9.5932 Å / Origin y: -0.8695 Å / Origin z: 16.3549 Å
111213212223313233
T0.1337 Å2-0.0219 Å20.0122 Å2-0.0715 Å20.0224 Å2--0.013 Å2
L1.8152 °20.4888 °2-0.6099 °2-2.6301 °2-0.039 °2--2.2344 °2
S0.0591 Å °-0.3471 Å °-0.1192 Å °0.5055 Å °-0.0916 Å °0.0648 Å °0.2686 Å °0.0243 Å °0.0325 Å °

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