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- PDB-8au5: c-MET F1200I mutant in complex with Tepotinib -

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Basic information

Entry
Database: PDB / ID: 8au5
Titlec-MET F1200I mutant in complex with Tepotinib
ComponentsHepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE / PROTEIN KINASE
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-3E8 / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.72 Å
AuthorsGraedler, U. / Lammens, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Biol.Chem. / Year: 2023
Title: Biophysical and structural characterization of the impacts of MET phosphorylation on tepotinib binding.
Authors: Gradler, U. / Schwarz, D. / Wegener, A. / Eichhorn, T. / Bandeiras, T.M. / Freitas, M.C. / Lammens, A. / Ganichkin, O. / Augustin, M. / Minguzzi, S. / Becker, F. / Bomke, J.
History
DepositionAug 25, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 6, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 22, 2023Group: Database references / Category: citation / Item: _citation.journal_volume

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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)34,6256
Polymers33,9101
Non-polymers7145
Water543
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)38.484, 43.173, 88.794
Angle α, β, γ (deg.)90.000, 91.670, 90.000
Int Tables number4
Space group name H-MP1211

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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: 33910.359 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-3E8 / 3-[1-(3-{5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl}benzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzonitrile


Mass: 492.572 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H28N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#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.: 3 / 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: 2.34 Å3/Da / Density % sol: 47.49 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7.6 / Details: PEG 8000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Apr 16, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.72→88.76 Å / Num. obs: 7637 / % possible obs: 95 % / Redundancy: 2.9 % / Rrim(I) all: 0.061 / Rsym value: 0.05 / Net I/σ(I): 14.16
Reflection shellResolution: 2.72→2.97 Å / Redundancy: 2.8 % / Mean I/σ(I) obs: 2.88 / Num. unique obs: 1783 / Rrim(I) all: 0.577 / Rsym value: 0.472 / % possible all: 96.7

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4R1V

4r1v


Resolution: 2.72→88.76 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.925 / SU B: 37.144 / SU ML: 0.359 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.447 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2778 746 9.8 %RANDOM
Rwork0.2343 ---
obs0.2386 6891 94.98 %-
Displacement parametersBiso max: 195.29 Å2 / Biso mean: 88.345 Å2 / Biso min: 29.81 Å2
Baniso -1Baniso -2Baniso -3
1--0.13 Å20 Å20.06 Å2
2--0.05 Å20 Å2
3---0.08 Å2
Refinement stepCycle: final / Resolution: 2.72→88.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2123 0 50 3 2176
Biso mean--75.52 37.48 -
Num. residues----265
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0222224
X-RAY DIFFRACTIONr_bond_other_d0.0020.021550
X-RAY DIFFRACTIONr_angle_refined_deg1.0521.9862998
X-RAY DIFFRACTIONr_angle_other_deg1.3533765
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4665260
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.5422.88990
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.39915387
X-RAY DIFFRACTIONr_dihedral_angle_4_deg9.9321513
X-RAY DIFFRACTIONr_chiral_restr0.0630.2330
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0212367
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02460
LS refinement shellResolution: 2.72→2.791 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.487 53 -
Rwork0.367 509 -
all-562 -
obs--96.73 %

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