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- PDB-1py5: Crystal Structure of TGF-beta receptor I kinase with inhibitor -

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Basic information

Entry
Database: PDB / ID: 1py5
TitleCrystal Structure of TGF-beta receptor I kinase with inhibitor
ComponentsTGF-beta receptor type I
KeywordsTRANSFERASE / TGF-beta / receptor I / kinase
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
4-(3-PYRIDIN-2-YL-1H-PYRAZOL-4-YL)QUINOLINE / TGF-beta receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsZhang, F. / Sawyer, J.S.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2004
Title: Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain.
Authors: Sawyer, J.S. / Beight, D.W. / Britt, K.S. / Anderson, B.D. / Campbell, R.M. / Goodson, T. / Herron, D.K. / Li, H.Y. / McMillen, W.T. / Mort, N. / Parsons, S. / Smith, E.C. / Wagner, J.R. / ...Authors: Sawyer, J.S. / Beight, D.W. / Britt, K.S. / Anderson, B.D. / Campbell, R.M. / Goodson, T. / Herron, D.K. / Li, H.Y. / McMillen, W.T. / Mort, N. / Parsons, S. / Smith, E.C. / Wagner, J.R. / Yan, L. / Zhang, F. / Yingling, J.M.
History
DepositionJul 8, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 13, 2004Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Aug 16, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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)37,4713
Polymers37,1031
Non-polymers3682
Water2,630146
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)41.829, 78.111, 90.686
Angle α, β, γ (deg.)90.0, 90.0, 90.0
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: 37102.590 Da / Num. of mol.: 1 / Fragment: Truncated kinase domain, residues 175-500
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFBR1 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P36897, EC: 2.7.1.37
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-PY1 / 4-(3-PYRIDIN-2-YL-1H-PYRAZOL-4-YL)QUINOLINE


Mass: 272.304 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H12N4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 146 / 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 Å3/Da / Density % sol: 38.38 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.6
Details: Tris, ATP, MgCl2, DTT, Hexanediol, PEG4000, LiSO4, pH 7.6, VAPOR DIFFUSION, HANGING DROP, temperature 298.0K

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Jun 10, 2000 / Details: mirrors
RadiationMonochromator: Yale Mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→20 Å / Num. all: 13208 / Num. obs: 13178 / % possible obs: 99.7 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 6 % / Biso Wilson estimate: 17.3 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 8
Reflection shellResolution: 2.3→2.44 Å / Redundancy: 4 % / Rmerge(I) obs: 0.185 / Mean I/σ(I) obs: 5 / Num. unique all: 1607 / % possible all: 74.7

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Processing

Software
NameClassification
HKL-2000data collection
SCALEPACKdata scaling
AMoREphasing
CNSrefinement
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1B6C

1b6c


Resolution: 2.3→20 Å / Isotropic thermal model: Isotropic / Cross valid method: THROUGHOUT / σ(F): 1 / Stereochemistry target values: Engh & Huber / Details: Used weighted full matrix least squares procedure
RfactorNum. reflectionSelection details
Rfree0.292 669 RANDOM
Rwork0.258 --
all0.26 13208 -
obs0.258 13178 -
Displacement parametersBiso mean: 21.4 Å2
Baniso -1Baniso -2Baniso -3
1-0.18 Å20 Å20 Å2
2--3.13 Å20 Å2
3----3.31 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.039 Å0.034 Å
Luzzati d res low-5 Å
Luzzati sigma a0.38 Å0.2 Å
Refinement stepCycle: LAST / Resolution: 2.3→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2418 0 26 146 2590
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.01
X-RAY DIFFRACTIONc_angle_deg1.5
X-RAY DIFFRACTIONc_dihedral_angle_d22.6
X-RAY DIFFRACTIONc_improper_angle_d0.85
X-RAY DIFFRACTIONc_mcbond_it1.51
X-RAY DIFFRACTIONc_mcangle_it2.5
LS refinement shellResolution: 2.3→2.44 Å / Rfactor Rfree error: 0.041
RfactorNum. reflection% reflection
Rfree0.31 79 -
Rwork0.267 --
obs-1607 74.7 %

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