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- PDB-1vjy: Crystal Structure of a Naphthyridine Inhibitor of Human TGF-beta ... -

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Basic information

Entry
Database: PDB / ID: 1vjy
TitleCrystal Structure of a Naphthyridine Inhibitor of Human TGF-beta Type I Receptor
ComponentsTGF-beta receptor type I
KeywordsTRANSFERASE / protein kinase / Inhibitor Complex
Function / homology
Function and homology information


extracellular structure organization / epicardium morphogenesis / vascular endothelial cell proliferation / parathyroid gland development / transforming growth factor beta ligand-receptor complex / regulation of cardiac muscle cell proliferation / myofibroblast differentiation / positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation / TGFBR2 Kinase Domain Mutants in Cancer / transforming growth factor beta receptor activity ...extracellular structure organization / epicardium morphogenesis / vascular endothelial cell proliferation / parathyroid gland development / transforming growth factor beta ligand-receptor complex / regulation of cardiac muscle cell proliferation / myofibroblast differentiation / positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation / TGFBR2 Kinase Domain Mutants in Cancer / transforming growth factor beta receptor activity / ventricular compact myocardium morphogenesis / trophoblast cell migration / positive regulation of mesenchymal stem cell proliferation / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / TGFBR3 regulates TGF-beta signaling / positive regulation of tight junction disassembly / cardiac epithelial to mesenchymal transition / mesenchymal cell differentiation / positive regulation of vasculature development / neuron fate commitment / activin receptor complex / positive regulation of extracellular matrix assembly / type II transforming growth factor beta receptor binding / 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 / pharyngeal system development / TGFBR1 LBD Mutants in Cancer / transforming growth factor beta receptor activity, type III / activin binding / regulation of epithelial to mesenchymal transition / coronary artery morphogenesis / angiogenesis involved in coronary vascular morphogenesis / germ cell migration / filopodium assembly / ventricular trabecula myocardium morphogenesis / activin receptor signaling pathway / response to cholesterol / embryonic cranial skeleton morphogenesis / I-SMAD binding / transforming growth factor beta binding / collagen fibril organization / negative regulation of chondrocyte differentiation / endothelial cell activation / anterior/posterior pattern specification / skeletal system morphogenesis / lens development in camera-type eye / positive regulation of filopodium assembly / artery morphogenesis / ventricular septum morphogenesis / SMAD binding / negative regulation of endothelial cell proliferation / roof of mouth development / TGF-beta receptor signaling activates SMADs / positive regulation of SMAD protein signal transduction / blastocyst development / regulation of protein ubiquitination / epithelial to mesenchymal transition / bicellular tight junction / endothelial cell migration / positive regulation of epithelial to mesenchymal transition / cellular response to transforming growth factor beta stimulus / positive regulation of stress fiber assembly / positive regulation of endothelial cell proliferation / transforming growth factor beta receptor signaling pathway / negative regulation of cell migration / thymus development / Downregulation of TGF-beta receptor signaling / positive regulation of apoptotic signaling pathway / post-embryonic development / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / kidney development / skeletal system development / negative regulation of extrinsic apoptotic signaling pathway / cell motility / wound healing / cellular response to growth factor stimulus / male gonad development / UCH proteinases / nervous system development / peptidyl-serine phosphorylation / heart development / regulation of gene expression / positive regulation of cell growth / in utero embryonic development / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / protein kinase activity / regulation of cell cycle / endosome / Ub-specific processing proteases / intracellular signal transduction / cilium / positive regulation of cell migration / membrane raft
Similarity search - Function
GS domain / Transforming growth factor beta type I GS-motif / GS domain profile. / GS motif / Activin types I and II receptor domain / Activin types I and II receptor domain / Ser/Thr protein kinase, TGFB receptor / Snake toxin-like superfamily / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 ...GS domain / Transforming growth factor beta type I GS-motif / GS domain profile. / GS motif / Activin types I and II receptor domain / Activin types I and II receptor domain / Ser/Thr protein kinase, TGFB receptor / Snake toxin-like superfamily / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-460 / TGF-beta receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2 Å
AuthorsGellibert, F. / Woolven, J. / Fouchet, M.-H. / Mathews, N. / Goodland, H. / Lovegrove, V. / Laroze, A. / Nguyen, V.-L. / Sautet, S. / Wang, R. ...Gellibert, F. / Woolven, J. / Fouchet, M.-H. / Mathews, N. / Goodland, H. / Lovegrove, V. / Laroze, A. / Nguyen, V.-L. / Sautet, S. / Wang, R. / Janson, C. / Smith, W. / Krysa, G. / Boullay, V. / de Gouville, A.-C. / Huet, S. / Hartley, D.
CitationJournal: J.Med.Chem. / Year: 2004
Title: Identification of 1,5-Naphthyridine Derivatives as a Novel Series of Potent and Selective TGF-beta Type I Receptor Inhibitors.
Authors: Gellibert, F. / Woolven, J. / Fouchet, M.-H. / Mathews, N. / Goodland, H. / Lovegrove, V. / Laroze, A. / Nguyen, V.-L. / Sautet, S. / Wang, R. / Janson, C. / Smith, W. / Krysa, G. / Boullay, ...Authors: Gellibert, F. / Woolven, J. / Fouchet, M.-H. / Mathews, N. / Goodland, H. / Lovegrove, V. / Laroze, A. / Nguyen, V.-L. / Sautet, S. / Wang, R. / Janson, C. / Smith, W. / Krysa, G. / Boullay, V. / De Gouville, A.-C. / Huet, S. / Hartley, D.
History
DepositionApr 7, 2004Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 31, 2004Provider: repository / Type: Initial release
Revision 1.1Apr 26, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Dec 27, 2023Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)35,0132
Polymers34,7241
Non-polymers2891
Water2,054114
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.069, 75.775, 89.589
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 I / TGFR-1 / TGF-beta type I receptor / Serine/threonine-protein kinase receptor R4 / SKR4 / Activin ...TGFR-1 / TGF-beta type I receptor / Serine/threonine-protein kinase receptor R4 / SKR4 / Activin receptor-like kinase 5 / ALK-5


Mass: 34723.992 Da / Num. of mol.: 1 / Fragment: protein kinase
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P36897, EC: 2.7.1.37
#2: Chemical ChemComp-460 / 2-[5-(6-METHYLPYRIDIN-2-YL)-2,3-DIHYDRO-1H-PYRAZOL-4-YL]-1,5-NAPHTHYRIDINE / NAPHTHYRIDINE INHIBITOR


Mass: 289.335 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H15N5
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 114 / Source method: isolated from a natural source / Formula: H2O

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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: 2.06 Å3/Da / Density % sol: 40.16 %
Crystal growTemperature: 278 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 20% PEG 4000, 0.1M Tris HCl, 0.2 M magnesium chloride, pH 8.0, vapor diffusion/sitting drop, temperature 278K, VAPOR DIFFUSION, SITTING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 1
DetectorType: MAR CCD 165 mm / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. all: 20019 / Num. obs: 17608 / % possible obs: 88 % / Observed criterion σ(I): 2 / Redundancy: 4.3 % / Rmerge(I) obs: 0.051
Reflection shellResolution: 2→2.04 Å / Rmerge(I) obs: 0.209

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Processing

Software
NameClassification
HKL-2000data collection
SCALEPACKdata scaling
CNXrefinement
HKL-2000data reduction
CNXphasing
RefinementResolution: 2→50 Å / σ(F): 2 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.275 854 -RANDOM
Rwork0.223 ---
all-20019 --
obs-17608 88 %-
Refinement stepCycle: LAST / Resolution: 2→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2406 0 22 114 2542
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d2
X-RAY DIFFRACTIONc_angle_deg2.5

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