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- PDB-8k78: Crystal structure of cMET kinase domain bound by TPX-0022 -

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Basic information

Entry
Database: PDB / ID: 8k78
TitleCrystal structure of cMET kinase domain bound by TPX-0022
ComponentsHepatocyte growth factor receptor
KeywordsTRANSFERASE / cMET / TPX-0022
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 / MET activates STAT3 / negative regulation of hydrogen peroxide-mediated programmed cell death / MET interacts with TNS proteins / MET Receptor Activation / endothelial cell morphogenesis / semaphorin receptor activity / MET receptor recycling ...hepatocyte growth factor receptor activity / 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 interacts with TNS proteins / MET Receptor Activation / 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 / 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 / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / phagocytosis / MECP2 regulates neuronal receptors and channels / positive regulation of microtubule polymerization / negative regulation of autophagy / basal plasma membrane / InlB-mediated entry of Listeria monocytogenes into host cell / excitatory postsynaptic potential / liver development / molecular function activator activity / Negative regulation of MET activity / receptor protein-tyrosine kinase / neuron differentiation / 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 tyrosine kinase activity / protein phosphatase binding / postsynapse / receptor complex / cell surface receptor signaling pathway / 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 / PSI domain / domain found in Plexins, Semaphorins and Integrins / IPT domain / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Immunoglobulin E-set / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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
: / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.67 Å
AuthorsQu, L.Z. / Chen, Y.H.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Comput Struct Biotechnol J / Year: 2023
Title: Structural insight into the macrocyclic inhibitor TPX-0022 of c-Met and c-Src.
Authors: Qu, L. / Lin, H. / Dai, S. / Guo, M. / Chen, X. / Jiang, L. / Zhang, H. / Li, M. / Liang, X. / Chen, Z. / Wei, H. / Chen, Y.
History
DepositionJul 26, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jul 31, 2024Provider: repository / Type: Initial release

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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)35,2522
Polymers34,8421
Non-polymers4091
Water1,11762
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)45.054, 66.625, 55.294
Angle α, β, γ (deg.)90.00, 107.00, 90.00
Int Tables number4
Space group name H-MP1211

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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: 34842.320 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Production host: Escherichia coli (E. coli)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-IYC / Elzovantinib / (11S)-16-amino-2-ethyl-6-fluoro-11-methyl-14-oxo-10-oxa-2,13,17,18,21-pentazatetracyclo[13.5.2.04,9.018,22]docosa-1(21),4(9),5,7,15(22),16,19-heptaene-5-carbonitrile / TPX-0022


Mass: 409.417 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C20H20FN7O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 62 / 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: 2.35 Å3/Da / Density % sol: 47.68 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / Details: 25% PEG 8K

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.9791 Å
DetectorType: ADSC QUANTUM 1 / Detector: CCD / Date: May 30, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 2.67→43.1 Å / Num. obs: 15491 / % possible obs: 95.8 % / Redundancy: 3.1 % / CC1/2: 0.972 / Net I/σ(I): 4.1
Reflection shellResolution: 2.67→2.765 Å / Num. unique obs: 873 / CC1/2: 0.772

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Processing

Software
NameVersionClassification
PHENIX(1.19.2_4158: ???)refinement
PHASER3.25phasing
XDSdata reduction
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.67→43.09 Å / SU ML: 0.32 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 30.56 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2898 1529 9.87 %
Rwork0.2386 --
obs0.2439 15491 88.55 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.67→43.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2285 0 30 62 2377
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032399
X-RAY DIFFRACTIONf_angle_d0.5363271
X-RAY DIFFRACTIONf_dihedral_angle_d15.432842
X-RAY DIFFRACTIONf_chiral_restr0.042370
X-RAY DIFFRACTIONf_plane_restr0.004413
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.67-2.750.34281460.3161317X-RAY DIFFRACTION92
2.75-2.850.35051430.28611307X-RAY DIFFRACTION93
2.85-2.970.31551460.2861329X-RAY DIFFRACTION92
2.97-3.10.33621480.28141325X-RAY DIFFRACTION92
3.1-3.270.33391420.26861282X-RAY DIFFRACTION91
3.27-3.470.31091340.27271232X-RAY DIFFRACTION85
3.47-3.740.3081230.24131218X-RAY DIFFRACTION84
3.74-4.110.27551350.20671196X-RAY DIFFRACTION85
4.11-4.710.26551300.18291200X-RAY DIFFRACTION83
4.71-5.930.25011360.20911245X-RAY DIFFRACTION87
5.93-43.090.21941460.19441311X-RAY DIFFRACTION92

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