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- PDB-7v3r: Crystal structure of CMET in complex with a novel inhibitor -

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Basic information

Entry
Database: PDB / ID: 7v3r
TitleCrystal structure of CMET in complex with a novel inhibitor
ComponentsHepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE/INHIBITOR / TRANSFERASE-INHIBITOR COMPLEX
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 / negative regulation of autophagy / basal plasma membrane / InlB-mediated entry of Listeria monocytogenes into host cell / liver development / molecular function activator activity / Negative regulation of MET activity / neuron differentiation / receptor protein-tyrosine kinase / 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 tyrosine kinase activity / protein phosphatase binding / 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-5IE / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.7 Å
AuthorsSu, H.X. / Liu, Q.F. / Chen, T.T. / Li, M.J. / Xu, Y.C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery of 10H-Benzo[b]pyrido[2,3-e][1,4]oxazine AXL Inhibitors via Structure-Based Drug Design Targeting c-Met Kinase
Authors: Zhan, Z. / Ji, Y. / Su, H. / Fang, C. / Peng, X. / Liu, Q. / Dai, Y. / Lin, D. / Xu, Y. / Ai, J. / Duan, W.
History
DepositionAug 11, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 17, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 8, 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Hepatocyte growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,5352
Polymers36,0341
Non-polymers5011
Water3,891216
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13310 Å2
Unit cell
Length a, b, c (Å)43.083, 80.833, 90.774
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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: 36033.594 Da / Num. of mol.: 1 / Fragment: UNP residues 1038-1346
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-5IE / ~{N}1'-[3-fluoranyl-4-(2-phenylazanylpyrimidin-4-yl)oxy-phenyl]-~{N}1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide


Mass: 501.484 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H21F2N5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 216 / 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: 2.19 Å3/Da / Density % sol: 43.92 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1 M HEPES, 8% isopropanol, 3 mM TECP, 16% PEG4000, pH7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.9785 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 10, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9785 Å / Relative weight: 1
ReflectionResolution: 1.7→50 Å / Num. obs: 35736 / % possible obs: 100 % / Redundancy: 7.1 % / Rmerge(I) obs: 0.093 / Χ2: 1.017 / Net I/σ(I): 8.8 / Num. measured all: 254375
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
1.7-1.737.20.42617730.841199.9
1.73-1.767.20.37117420.8821100
1.76-1.797.20.35317890.9251100
1.79-1.837.20.30217170.921100
1.83-1.877.20.25717750.964199.9
1.87-1.917.30.22717320.9591100
1.91-1.967.30.2117891.0121100
1.96-2.027.30.18717491.018199.9
2.02-2.077.30.15417801.0371100
2.07-2.147.30.13717631.0311100
2.14-2.227.30.1217621.017199.9
2.22-2.317.20.10917721.0181100
2.31-2.417.20.10317881.0431100
2.41-2.547.10.10118041.1661100
2.54-2.77.10.10117831.3271100
2.7-2.916.90.09117791.3551100
2.91-3.26.80.0818071.3741100
3.2-3.666.80.06318291.0851100
3.66-4.616.90.05518400.94199.8
4.61-506.70.05719630.479199.6

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation5.9 Å35.07 Å

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Processing

Software
NameVersionClassification
PHENIX1.17.1-3660refinement
SCALEPACKdata scaling
PHASER2.8.3phasing
PDB_EXTRACT3.27data extraction
DIALSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4GG5
Resolution: 1.7→35.07 Å / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 16.43 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1896 1750 4.93 %
Rwork0.1675 33774 -
obs0.1686 35524 99.5 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 53.64 Å2 / Biso mean: 18.6094 Å2 / Biso min: 4.54 Å2
Refinement stepCycle: final / Resolution: 1.7→35.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2200 0 37 216 2453
Biso mean--12.33 27.39 -
Num. residues----285
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 12

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.7-1.750.19051320.17772644277695
1.75-1.810.21721420.17542759290199
1.81-1.870.22521610.164927932954100
1.87-1.950.18051510.166627712922100
1.95-2.030.19341620.163427692931100
2.03-2.140.16941440.156128112955100
2.14-2.280.17171220.157228312953100
2.28-2.450.21451400.164828222962100
2.45-2.70.15441520.173628312983100
2.7-3.090.21291640.172128202984100
3.09-3.890.18911480.16528823030100
3.89-35.070.18571320.17230413173100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
13.0239-3.76781.05847.1534-3.83852.9571-0.17140.17170.46940.3239-0.139-0.5724-0.34910.26130.2940.2087-0.06480.01040.15570.06720.240317.7756-0.205-38.9511
25.4802-0.1867-1.094.432-0.26134.60680.07980.5503-0.1879-0.644-0.0510.14250.4365-0.3855-0.03250.2514-0.0189-0.0180.16250.01790.082811.4039-19.8268-41.2959
32.7611-1.1526-0.20416.6904-0.25173.1279-0.00180.20680.1199-0.1234-0.04840.1855-0.20080.05060.0350.1378-0.02950.01890.14560.05270.077112.4552-10.2319-36.8746
41.0241-0.2331-0.21641.3839-1.51124.74920.0717-0.00840.14-0.0102-0.1693-0.0909-0.44710.57060.08150.1672-0.08560.01530.20020.0280.131917.1284-11.0563-31.9157
50.7712-0.0882-0.68240.557-1.04543.8550.01770.0579-0.024-0.1227-0.0759-0.01260.09980.18560.0430.0654-0.0256-0.00610.09460.00450.102310.0362-20.6814-20.1874
62.0056-1.2759-2.90684.84163.79642.0080.04160.8496-0.059-0.63750.0620.3659-0.1909-0.7234-0.13290.2725-0.0176-0.03280.33170.04950.224-4.6227-14.1031-27.0135
72.9034-0.27340.14753.75520.07432.4422-0.03310.19650.1179-0.1631-0.05710.2122-0.1543-0.2790.090.0722-0.0133-0.01650.12290.00870.076-3.0335-14.1502-13.718
83.8995-0.84360.10311.676-0.30231.4423-0.01930.07240.05950.01560.03360.0764-0.0688-0.0338-0.01220.0505-0.01940.00030.0565-0.00080.03590.884-17.2467-4.6095
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 1053 through 1072 )A0
2X-RAY DIFFRACTION2chain 'A' and (resid 1073 through 1098 )A0
3X-RAY DIFFRACTION3chain 'A' and (resid 1099 through 1131 )A0
4X-RAY DIFFRACTION4chain 'A' and (resid 1132 through 1153 )A0
5X-RAY DIFFRACTION5chain 'A' and (resid 1154 through 1224 )A0
6X-RAY DIFFRACTION6chain 'A' and (resid 1225 through 1246 )A0
7X-RAY DIFFRACTION7chain 'A' and (resid 1247 through 1288 )A0
8X-RAY DIFFRACTION8chain 'A' and (resid 1289 through 1346 )A0

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