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- PDB-8au3: c-MET Y1234E,Y1235E mutant in complex with Tepotinib -

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Basic information

Entry
Database: PDB / ID: 8au3
Titlec-MET Y1234E,Y1235E mutant in complex with Tepotinib
ComponentsHepatocyte growth factor receptor
KeywordsTRANSFERASE / PROTEIN KINASE
Function / homology
Function and homology information


negative regulation of guanyl-nucleotide exchange factor activity / Drug-mediated inhibition of MET activation / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET Receptor Activation / MET interacts with TNS proteins / endothelial cell morphogenesis / semaphorin receptor activity / MET receptor recycling / pancreas development ...negative regulation of guanyl-nucleotide exchange factor activity / Drug-mediated inhibition of MET activation / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET Receptor Activation / MET interacts with TNS proteins / endothelial cell morphogenesis / semaphorin receptor activity / 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 / positive regulation of endothelial cell chemotaxis / MET activates PTK2 signaling / branching morphogenesis of an epithelial tube / positive chemotaxis / negative regulation of Rho protein signal transduction / negative regulation of thrombin-activated receptor signaling pathway / semaphorin-plexin signaling pathway / establishment of skin barrier / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / MET activates RAS signaling / phagocytosis / MECP2 regulates neuronal receptors and channels / positive regulation of microtubule polymerization / negative regulation of autophagy / liver development / basal plasma membrane / InlB-mediated entry of Listeria monocytogenes into host cell / molecular function activator activity / excitatory postsynaptic potential / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / GPI-linked ephrin receptor activity / transmembrane-ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor 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 / protein tyrosine kinase activity / RAF/MAP kinase cascade / protein phosphatase binding / histone H3Y41 kinase activity / histone H2AXY142 kinase activity / receptor complex / cell surface receptor signaling pathway / postsynapse / cell surface / signal transduction / positive regulation of transcription by RNA polymerase II / extracellular region / ATP binding / identical protein binding / membrane / 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 / IPT domain / PSI domain / domain found in Plexins, Semaphorins and Integrins / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Immunoglobulin E-set / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-3E8 / DI(HYDROXYETHYL)ETHER / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.26 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

Downloads & links

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Assembly

Deposited unit
A: Hepatocyte growth factor receptor
B: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,0386
Polymers67,7532
Non-polymers1,2854
Water1,45981
1
A: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3692
Polymers33,8761
Non-polymers4931
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,6694
Polymers33,8761
Non-polymers7933
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)116.676, 139.120, 240.116
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number22
Space group name H-MF222
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: SER / Beg label comp-ID: SER / End auth comp-ID: HIS / End label comp-ID: HIS / Refine code: _ / Auth seq-ID: 1056 - 1348 / Label seq-ID: 6 - 298

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

#1: Protein Hepatocyte growth factor receptor / 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: 33876.254 Da / Num. of mol.: 2
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.: 2 / Source method: obtained synthetically / Formula: C29H28N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#4: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 81 / 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: 3.63 Å3/Da / Density % sol: 66.17 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5 / Details: 3.4 M NaFormiate, 0.1 M MES

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.00004 Å
DetectorType: DECTRIS EIGER R 1M / Detector: PIXEL / Date: Aug 26, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00004 Å / Relative weight: 1
ReflectionResolution: 2.257→120.06 Å / Num. obs: 28169 / % possible obs: 92.2 % / Redundancy: 8.2 % / CC1/2: 0.999 / Rmerge(I) obs: 0.087 / Rpim(I) all: 0.032 / Rrim(I) all: 0.092 / Rsym value: 0.087 / Net I/σ(I): 14.9
Reflection shellResolution: 2.257→2.542 Å / Redundancy: 7.2 % / Rmerge(I) obs: 1.182 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 1408 / CC1/2: 0.634 / Rpim(I) all: 0.462 / Rrim(I) all: 1.272 / Rsym value: 1.182 / % possible all: 66.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0155refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
autoPROCdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4R1V

4r1v


Resolution: 2.26→120.06 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.917 / SU B: 14.621 / SU ML: 0.176 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.376 / ESU R Free: 0.263 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2397 822 2.9 %RANDOM
Rwork0.1967 ---
obs0.198 27348 61.38 %-
Displacement parametersBiso max: 178.06 Å2 / Biso mean: 71.664 Å2 / Biso min: 32.61 Å2
Baniso -1Baniso -2Baniso -3
1-0.58 Å2-0 Å2-0 Å2
2---0.09 Å2-0 Å2
3----0.49 Å2
Refinement stepCycle: final / Resolution: 2.26→120.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4510 0 94 82 4686
Biso mean--60.47 55.14 -
Num. residues----566
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0194621
X-RAY DIFFRACTIONr_bond_other_d0.0030.024449
X-RAY DIFFRACTIONr_angle_refined_deg1.571.9796266
X-RAY DIFFRACTIONr_angle_other_deg1.235310180
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5515562
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.80722.688186
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.46315.105763
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.2371525
X-RAY DIFFRACTIONr_chiral_restr0.090.2701
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0215097
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021078
Refine LS restraints NCS

Ens-ID: 1 / Number: 6320 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.05 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.26→2.316 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.435 2 -
Rwork0.318 61 -
obs--1.87 %

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