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- PDB-7dv6: Discovery of Functionally Selective Transforming Growth Factor be... -

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Basic information

Entry
Database: PDB / ID: 7dv6
TitleDiscovery of Functionally Selective Transforming Growth Factor beta Type II Receptor (TGF-beta RII) Inhibitors as Anti-Fibrosis Agents
ComponentsTGF-beta receptor type-2
KeywordsIMMUNE SYSTEM / Inhibitor / Complex
Function / homology
Function and homology information


positive regulation of tolerance induction to self antigen / positive regulation of B cell tolerance induction / inferior endocardial cushion morphogenesis / bronchus morphogenesis / mammary gland morphogenesis / lens fiber cell apoptotic process / growth plate cartilage chondrocyte growth / tricuspid valve morphogenesis / TGFBR2 MSI Frameshift Mutants in Cancer / miRNA transport ...positive regulation of tolerance induction to self antigen / positive regulation of B cell tolerance induction / inferior endocardial cushion morphogenesis / bronchus morphogenesis / mammary gland morphogenesis / lens fiber cell apoptotic process / growth plate cartilage chondrocyte growth / tricuspid valve morphogenesis / TGFBR2 MSI Frameshift Mutants in Cancer / miRNA transport / transforming growth factor beta ligand-receptor complex / type III transforming growth factor beta receptor binding / aorta morphogenesis / positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation / Langerhans cell differentiation / TGFBR2 Kinase Domain Mutants in Cancer / transforming growth factor beta receptor activity / cardiac left ventricle morphogenesis / secondary palate development / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / endocardial cushion fusion / positive regulation of T cell tolerance induction / membranous septum morphogenesis / TGFBR3 regulates TGF-beta signaling / lung lobe morphogenesis / positive regulation of NK T cell differentiation / activin receptor complex / transforming growth factor beta receptor activity, type I / activin receptor activity, type I / activin receptor activity, type II / BMP receptor activity / receptor protein serine/threonine kinase / transmembrane receptor protein serine/threonine kinase activity / transforming growth factor beta receptor activity, type II / TGFBR1 LBD Mutants in Cancer / myeloid dendritic cell differentiation / transforming growth factor beta receptor activity, type III / activin binding / regulation of stem cell proliferation / type I transforming growth factor beta receptor binding / SMAD protein signal transduction / outflow tract septum morphogenesis / activin receptor signaling pathway / glycosaminoglycan binding / positive regulation of CD4-positive, alpha-beta T cell proliferation / regulation of stem cell differentiation / response to cholesterol / embryonic cranial skeleton morphogenesis / transforming growth factor beta binding / kinase activator activity / aortic valve morphogenesis / atrioventricular valve morphogenesis / lens development in camera-type eye / embryonic hemopoiesis / positive regulation of mesenchymal cell proliferation / artery morphogenesis / trachea formation / smoothened signaling pathway / branching involved in blood vessel morphogenesis / ventricular septum morphogenesis / blood vessel development / SMAD binding / heart looping / roof of mouth development / outflow tract morphogenesis / TGF-beta receptor signaling activates SMADs / positive regulation of epithelial cell migration / positive regulation of SMAD protein signal transduction / epithelial to mesenchymal transition / vasculogenesis / positive regulation of epithelial to mesenchymal transition / Notch signaling pathway / gastrulation / transforming growth factor beta receptor signaling pathway / Downregulation of TGF-beta receptor signaling / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / brain development / cellular response to growth factor stimulus / caveola / positive regulation of angiogenesis / positive regulation of reactive oxygen species metabolic process / UCH proteinases / nervous system development / regulation of cell population proliferation / heart development / regulation of gene expression / molecular adaptor activity / in utero embryonic development / receptor complex / nuclear body / membrane raft / response to xenobiotic stimulus / external side of plasma membrane / protein serine/threonine kinase activity / apoptotic process / positive regulation of cell population proliferation / extracellular space / extracellular region / ATP binding
Similarity search - Function
Transforming growth factor beta receptor 2 ectodomain / Transforming growth factor-beta receptor, type II / Transforming growth factor beta receptor 2 ectodomain / Ser/Thr protein kinase, TGFB receptor / Snake toxin-like superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Serine/Threonine protein kinases, catalytic domain ...Transforming growth factor beta receptor 2 ectodomain / Transforming growth factor-beta receptor, type II / Transforming growth factor beta receptor 2 ectodomain / Ser/Thr protein kinase, TGFB receptor / Snake toxin-like superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-HJF / TGF-beta receptor type-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.39 Å
AuthorsNishihata, J. / Nomura, A. / Miwa, S. / Doi, S. / Adachi, T.
CitationJournal: Acs Med.Chem.Lett. / Year: 2021
Title: Discovery of Selective Transforming Growth Factor beta Type II Receptor Inhibitors as Antifibrosis Agents.
Authors: Miwa, S. / Yokota, M. / Ueyama, Y. / Maeda, K. / Ogoshi, Y. / Seki, N. / Ogawa, N. / Nishihata, J. / Nomura, A. / Adachi, T. / Kitao, Y. / Nozawa, K. / Ishikawa, T. / Ukaji, Y. / Shiozaki, M.
History
DepositionJan 12, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 16, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: TGF-beta receptor type-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,1422
Polymers36,7881
Non-polymers3541
Water3,639202
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)61.973, 76.008, 77.980
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein TGF-beta receptor type-2 / TGFR-2 / TGF-beta type II receptor / Transforming growth factor-beta receptor type II / TbetaR-II


Mass: 36787.703 Da / Num. of mol.: 1 / Mutation: E431A,R433A,E485A,K488A,R493A,R495A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFBR2 / Production host: Escherichia coli (E. coli)
References: UniProt: P37173, receptor protein serine/threonine kinase
#2: Chemical ChemComp-HJF / 5-[(3S)-5,5-dimethyloxolan-3-yl]-6-methoxy-3-(2-methoxypyridin-4-yl)pyrazolo[1,5-a]pyrimidine


Mass: 354.403 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H22N4O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 202 / 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: 2.5 Å3/Da / Density % sol: 50.73 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 12-22% PEG4000,3% Ethylene Glycol,16% glycerol, 160 mM MgCl2, 80 mM TrisHCl at pH 7.5-9.3,The 9.2 mg/mL of TGFbetaRII protein was incubated with 1mM compound at 277K for 1-2 hr
PH range: 7.5-9.3

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 X 4M / Detector: PIXEL / Date: Jun 8, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.39→48.53 Å / Num. obs: 15148 / % possible obs: 99.9 % / Redundancy: 6.7 % / CC1/2: 0.998 / Rmerge(I) obs: 0.082 / Net I/σ(I): 19
Reflection shellResolution: 2.39→2.48 Å / Redundancy: 6.9 % / Rmerge(I) obs: 0.27 / Mean I/σ(I) obs: 7.6 / Num. unique obs: 1554 / CC1/2: 0.895 / % possible all: 99.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5E8V

5e8v


Resolution: 2.39→28.81 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.924 / SU B: 11.985 / SU ML: 0.148 / Cross valid method: THROUGHOUT / ESU R: 0.328 / ESU R Free: 0.234 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.22391 762 5 %RANDOM
Rwork0.15967 ---
obs0.1628 14345 99.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 46.599 Å2
Baniso -1Baniso -2Baniso -3
1-4.37 Å20 Å20 Å2
2---1.33 Å20 Å2
3----3.05 Å2
Refinement stepCycle: 1 / Resolution: 2.39→28.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2405 0 26 202 2633
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0122510
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.1431.6483413
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg1.8421.1883
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.45323.15127
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.1515432
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.7381513
X-RAY DIFFRACTIONr_chiral_restr0.1890.2323
X-RAY DIFFRACTIONr_gen_planes_refined0.0190.021911
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.9113.3481230
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it4.4465.0041541
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.9533.5391280
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined8.90459.09910806
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.39→2.452 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.229 56 -
Rwork0.192 1052 -
obs--99.91 %
Refinement TLS params.Method: refined / Origin x: 17.122 Å / Origin y: 6.405 Å / Origin z: 13.723 Å
111213212223313233
T0.0029 Å20.0128 Å20.0018 Å2-0.1259 Å20.0029 Å2--0.0774 Å2
L0.8856 °2-0.0671 °20.1148 °2-1.3554 °20.0734 °2--0.8901 °2
S-0.0005 Å °0.0236 Å °-0.0167 Å °0.0043 Å °-0.0049 Å °0.1497 Å °-0.0408 Å °-0.0476 Å °0.0055 Å °

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