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- PDB-9ivb: Crystal structure of c-Met kinase domain bound by bozitinib -

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Basic information

Entry
Database: PDB / ID: 9ivb
TitleCrystal structure of c-Met kinase domain bound by bozitinib
ComponentsHepatocyte growth factor receptor
KeywordsTRANSFERASE / c-Met / Bozitinib
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 / MET activates RAS signaling / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / MECP2 regulates neuronal receptors and channels / positive regulation of microtubule polymerization / negative regulation of autophagy / cell surface receptor protein tyrosine kinase signaling pathway / liver development / molecular function activator activity / InlB-mediated entry of Listeria monocytogenes into host cell / basal plasma membrane / 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 / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / Negative regulation of MET activity / neuron differentiation / Constitutive Signaling by Aberrant PI3K in Cancer / PIP3 activates AKT signaling / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / protein phosphatase binding / 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 / 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: 2.35 Å
AuthorsLin, H. / Chen, Y.H.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Commun Biol / Year: 2025
Title: Characterization of Bozitinib as a potential therapeutic agent for MET-amplified gastric cancer.
Authors: Lin, H. / Qu, L. / Wei, H. / Guo, M. / Chen, X. / Lin, Q. / Zhang, H. / Dai, S. / Chen, Y.
History
DepositionJul 23, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 22, 2025Provider: repository / Type: Initial release
Revision 1.1Feb 12, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)70,5334
Polymers69,6852
Non-polymers8492
Water1,29772
1
A: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2672
Polymers34,8421
Non-polymers4241
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2672
Polymers34,8421
Non-polymers4241
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)54.568, 66.168, 79.617
Angle α, β, γ (deg.)90.00, 91.69, 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.: 2 / Fragment: kinase domain
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-A1L3A / bozitinib / 9-[bis(fluoranyl)-(6-fluoranyl-2-methyl-indazol-5-yl)methyl]-3-(1-cyclopropylpyrazol-4-yl)-1$l^{4},2,7,8-tetrazabicyclo[4.3.0]nona-1,3,5,8-tetraene / Vebreltinib


Mass: 424.382 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H15F3N8 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 72 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.13 Å3/Da / Density % sol: 42.23 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.8 / Details: 15-30% PEG8K

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97851 Å
DetectorType: ADSC QUANTUM 1 / Detector: CCD / Date: Jan 2, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97851 Å / Relative weight: 1
ReflectionResolution: 2.35→34.13 Å / Num. obs: 23820 / % possible obs: 99.9 % / Redundancy: 6.5 % / CC1/2: 0.97 / Net I/σ(I): 4.1
Reflection shellResolution: 2.35→2.41 Å / Num. unique obs: 1746 / CC1/2: 0.639

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Processing

Software
NameVersionClassification
PHENIX(1.19.2_4158: ???)refinement
xia2data reduction
xia2data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5EOB

5eob


Resolution: 2.35→34.1 Å / Cross valid method: FREE R-VALUE / σ(F): 83.23 / Phase error: 37.15 / Stereochemistry target values: TWIN_LSQ_F
RfactorNum. reflection% reflection
Rfree0.273 2036 8.55 %
Rwork0.2482 --
obs0.2834 23807 99.75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.35→34.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4600 0 62 72 4734
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0064786
X-RAY DIFFRACTIONf_angle_d0.796522
X-RAY DIFFRACTIONf_dihedral_angle_d7.884672
X-RAY DIFFRACTIONf_chiral_restr0.046742
X-RAY DIFFRACTIONf_plane_restr0.005814
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.35-2.410.31531310.31831511X-RAY DIFFRACTION90
2.41-2.470.31611440.29971555X-RAY DIFFRACTION92
2.47-2.540.3151450.30241523X-RAY DIFFRACTION91
2.54-2.630.27531340.30861571X-RAY DIFFRACTION92
2.63-2.720.33011440.30451572X-RAY DIFFRACTION92
2.72-2.830.36071510.30411525X-RAY DIFFRACTION91
2.83-2.960.32861360.3091569X-RAY DIFFRACTION92
2.96-3.110.3061430.30431542X-RAY DIFFRACTION92
3.11-3.310.34171470.30031565X-RAY DIFFRACTION91
3.31-3.560.30621450.28771544X-RAY DIFFRACTION91
3.56-3.920.29721410.27491584X-RAY DIFFRACTION92
3.92-4.490.25541420.2491558X-RAY DIFFRACTION91
4.49-5.650.28571450.24481574X-RAY DIFFRACTION92
5.65-34.10.24411500.2511616X-RAY DIFFRACTION91

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