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- PDB-5dg5: CRYSTAL STRUCTURE OF THE TYROSINE KINASE DOMAIN OF THE HEPATOCYTE... -

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Basic information

Entry
Database: PDB / ID: 5dg5
TitleCRYSTAL STRUCTURE OF THE TYROSINE KINASE DOMAIN OF THE HEPATOCYTE GROWTH FACTOR RECEPTOR C-MET IN COMPLEX WITH ALTIRATINIB ANALOG DP-4157
ComponentsHepatocyte growth factor receptorC-Met
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / TYROSINE KINASE DOMAIN / HEPATOCYTE GROWTH FACTOR RECEPTOR C-MET / C-MET / ALTIRATINIB ANALOG / DP-4157 / TRANSFERASE-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 / basal plasma membrane / negative regulation of autophagy / InlB-mediated entry of Listeria monocytogenes into host cell / liver development / molecular function activator 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 / RAF/MAP kinase cascade / protein phosphatase binding / protein tyrosine kinase activity / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-5B4 / Hepatocyte growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsSmith, B.D. / Kaufman, M.D. / Leary, C.B. / Turner, B.A. / Wise, S.A. / Ahn, Y.M. / Booth, R.J. / Caldwell, T.M. / Ensinger, C.L. / Hood, M.M. ...Smith, B.D. / Kaufman, M.D. / Leary, C.B. / Turner, B.A. / Wise, S.A. / Ahn, Y.M. / Booth, R.J. / Caldwell, T.M. / Ensinger, C.L. / Hood, M.M. / Lu, W.-P. / Patt, T.W. / Patt, W.C. / Rutkoski, T.J. / Samarakoon, T. / Telikepalli, H. / Vogeti, L. / Vogeti, S. / Yates, K.M. / Chun, L. / Stewart, L.J. / Clare, M. / Flynn, D.L.
CitationJournal: Mol.Cancer Ther. / Year: 2015
Title: Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2.
Authors: Smith, B.D. / Kaufman, M.D. / Leary, C.B. / Turner, B.A. / Wise, S.C. / Ahn, Y.M. / Booth, R.J. / Caldwell, T.M. / Ensinger, C.L. / Hood, M.M. / Lu, W.P. / Patt, T.W. / Patt, W.C. / ...Authors: Smith, B.D. / Kaufman, M.D. / Leary, C.B. / Turner, B.A. / Wise, S.C. / Ahn, Y.M. / Booth, R.J. / Caldwell, T.M. / Ensinger, C.L. / Hood, M.M. / Lu, W.P. / Patt, T.W. / Patt, W.C. / Rutkoski, T.J. / Samarakoon, T. / Telikepalli, H. / Vogeti, L. / Vogeti, S. / Yates, K.M. / Chun, L. / Stewart, L.J. / Clare, M. / Flynn, D.L.
History
DepositionAug 27, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 31, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_nonpoly / pdbx_initial_refinement_model / pdbx_struct_oper_list / struct_ncs_dom_lim
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _pdbx_struct_oper_list.symmetry_operation / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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)72,9964
Polymers71,9812
Non-polymers1,0152
Water59433
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area340 Å2
ΔGint-2 kcal/mol
Surface area28420 Å2
Unit cell
Length a, b, c (Å)37.130, 115.880, 90.160
Angle α, β, γ (deg.)90.000, 92.920, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 0 / Ens-ID: 1 / Beg auth comp-ID: THR / Beg label comp-ID: THR / End auth comp-ID: GLY / End label comp-ID: GLY / Refine code: 0 / Auth seq-ID: 1050 - 1346 / Label seq-ID: 22 - 318

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

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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: 35990.633 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MET / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P08581, receptor protein-tyrosine kinase
#2: Chemical ChemComp-5B4 / N-(2,5-difluoro-4-{[2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxam ide / ALTIRATINIB ANALOG DP-4157


Mass: 507.464 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C26H20F3N5O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 33 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.69 Å3/Da / Density % sol: 54 %
Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop
Details: Protein at 9.5mg/ml in 20 mM Tris pH 8.5, 100mM NaCl, 14mM 2-mercaptoethanol with 5-molar excess of compound; crystallization condition: 1.0M diammonium hydrogen phosphate, 0.2M sodium ...Details: Protein at 9.5mg/ml in 20 mM Tris pH 8.5, 100mM NaCl, 14mM 2-mercaptoethanol with 5-molar excess of compound; crystallization condition: 1.0M diammonium hydrogen phosphate, 0.2M sodium chloride, 0.1M citrate pH 5.0 and 7.5% glycerol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.9999 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 17, 2009
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.6→20 Å / Num. obs: 23076 / % possible obs: 98.3 % / Observed criterion σ(I): -3 / Redundancy: 3.2 % / Biso Wilson estimate: 47.861 Å2 / Rmerge F obs: 0.211 / Rmerge(I) obs: 0.1 / Rrim(I) all: 0.12 / Χ2: 0.96 / Net I/σ(I): 11.36 / Num. measured all: 73855
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Highest resolution (Å)Redundancy (%)Rmerge F obsRmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible all
2.6-2.783.20.9790.6891.9713508424942210.82799.3
2.78-30.6170.4293.1212526392338990.51599.4
3-3.290.3110.2195.9711579366136250.26399
3.29-3.680.1490.10911.1410485333032830.13198.6
3.68-4.250.0810.06217.649125289528370.07498
4.25-5.20.0540.044237624244723820.05297.3
5.2-7.350.0540.04522.615869191918530.05496.6
7.350.0230.02437.65313910639760.02991.8

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
PHASERphasing
Cootmodel building
REFMAC5.8.0073refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 2g15

2g15


Resolution: 2.6→19.65 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.917 / WRfactor Rfree: 0.2096 / WRfactor Rwork: 0.1759 / FOM work R set: 0.755 / SU B: 14.157 / SU ML: 0.283 / SU R Cruickshank DPI: 0.6743 / SU Rfree: 0.3023 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.674 / ESU R Free: 0.302 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2449 1161 5 %RANDOM
Rwork0.2036 ---
obs0.2057 21913 98.25 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 103.15 Å2 / Biso mean: 43.412 Å2 / Biso min: 15.89 Å2
Baniso -1Baniso -2Baniso -3
1--1.37 Å20 Å2-0.51 Å2
2---3.3 Å20 Å2
3---4.69 Å2
Refinement stepCycle: final / Resolution: 2.6→19.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4603 0 74 33 4710
Biso mean--33.08 37.24 -
Num. residues----594
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0194812
X-RAY DIFFRACTIONr_bond_other_d0.0030.024537
X-RAY DIFFRACTIONr_angle_refined_deg1.1961.9496554
X-RAY DIFFRACTIONr_angle_other_deg0.8932.98810405
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5155594
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.05123.211190
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.75815767
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.5211523
X-RAY DIFFRACTIONr_chiral_restr0.0770.2737
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0215390
X-RAY DIFFRACTIONr_gen_planes_other0.0040.021131
X-RAY DIFFRACTIONr_mcbond_it2.2584.3762376
X-RAY DIFFRACTIONr_mcbond_other2.2554.3752375
X-RAY DIFFRACTIONr_mcangle_it3.8236.5622967
Refine LS restraints NCS

Ens-ID: 1 / Number: 17561 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.08 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.6→2.666 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.376 72 -
Rwork0.349 1650 -
all-1722 -
obs--99.6 %

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