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- PDB-8gvj: Crystal structure of cMET kinase domain bound by D6808 -

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Basic information

Entry
Database: PDB / ID: 8gvj
TitleCrystal structure of cMET kinase domain bound by D6808
ComponentsHepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE/INHIBITOR / Inhibitor / TRANSFERASE / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


hepatocyte growth factor receptor activity / Drug-mediated inhibition of MET activation / MET activates STAT3 / endothelial cell morphogenesis / negative regulation of hydrogen peroxide-mediated programmed cell death / negative regulation of guanyl-nucleotide exchange factor activity / MET interacts with TNS proteins / MET Receptor Activation / positive regulation of endothelial cell chemotaxis / semaphorin receptor activity ...hepatocyte growth factor receptor activity / Drug-mediated inhibition of MET activation / MET activates STAT3 / endothelial cell morphogenesis / negative regulation of hydrogen peroxide-mediated programmed cell death / negative regulation of guanyl-nucleotide exchange factor activity / MET interacts with TNS proteins / MET Receptor Activation / positive regulation of endothelial cell chemotaxis / semaphorin receptor activity / MET receptor recycling / Sema4D mediated inhibition of cell attachment and migration / MET activates PTPN11 / pancreas development / MET activates RAP1 and RAC1 / MET activates PI3K/AKT signaling / negative regulation of Rho protein signal transduction / negative regulation of stress fiber assembly / semaphorin-plexin signaling pathway / MET activates PTK2 signaling / negative regulation of thrombin-activated receptor signaling pathway / branching morphogenesis of an epithelial tube / positive chemotaxis / establishment of skin barrier / MET activates RAS signaling / MECP2 regulates neuronal receptors and channels / phagocytosis / positive regulation of microtubule polymerization / negative regulation of autophagy / basal plasma membrane / InlB-mediated entry of Listeria monocytogenes into host cell / liver development / molecular function activator activity / neuron differentiation / Negative regulation of MET activity / receptor protein-tyrosine kinase / transmembrane receptor protein tyrosine kinase activity / positive regulation of kinase activity / Constitutive Signaling by Aberrant PI3K in Cancer / PIP3 activates AKT signaling / nervous system development / transmembrane receptor protein tyrosine kinase signaling pathway / cell migration / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein phosphatase binding / protein tyrosine kinase activity / positive regulation of protein kinase B signaling / cell surface receptor signaling pathway / receptor complex / 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-KGL / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.71 Å
AuthorsChen, Y.H. / Qu, L.Z.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery of D6808, a Highly Selective and Potent Macrocyclic c-Met Inhibitor for Gastric Cancer Harboring MET Gene Alteration Treatment.
Authors: Wang, C. / Li, J. / Qu, L. / Tang, X. / Song, X. / Yang, F. / Chen, X. / Lin, Q. / Lin, W. / Zhou, Y. / Tu, Z. / Chen, Y. / Zhang, Z. / Lu, X.
History
DepositionSep 15, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 23, 2022Provider: repository / Type: Initial release
Revision 1.1Dec 7, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)35,4012
Polymers34,8421
Non-polymers5591
Water57632
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.078, 66.078, 187.302
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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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: 34842.320 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: Escherichia coli (E. coli)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-KGL / (1^4Z,5^2E)-6^3-(trifluoromethyl)-5^1,5^6-dihydro-1^1H-8-aza-2(3,6)-quinolina-5(1,3)-pyridazina-1(4,1)-pyrazola-6(1,4)-benzenacyclododecaphane-5^6,7-dione


Mass: 558.554 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H25F3N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 32 / 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: 2.93 Å3/Da / Density % sol: 58.08 %
Crystal growTemperature: 291 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: BL02U1 / Wavelength: 0.979183 Å
DetectorType: ADSC QUANTUM 1 / Detector: CCD / Date: Sep 8, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979183 Å / Relative weight: 1
ReflectionResolution: 2.71→45.38 Å / Num. obs: 23949 / % possible obs: 99.88 % / Redundancy: 11.4 % / CC1/2: 0.997 / Rmerge(I) obs: 0.0316 / Net I/σ(I): 13.31
Reflection shellResolution: 2.71→2.807 Å / Num. unique obs: 2336 / CC1/2: 0.896

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6SDE
Resolution: 2.71→45.38 Å / SU ML: 0.39 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 25.73 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2617 598 4.99 %
Rwork0.2185 11385 -
obs0.2206 11983 99.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 111.99 Å2 / Biso mean: 55.7089 Å2 / Biso min: 30.66 Å2
Refinement stepCycle: final / Resolution: 2.71→45.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2249 0 41 32 2322
Biso mean--50.82 51.39 -
Num. residues----285
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 4 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
2.71-2.980.35911510.268927672918
2.98-3.410.30781440.250727842928
3.41-4.30.23061470.21428192966
4.3-45.380.24711560.200930153171

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