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- PDB-3kcf: Crystal structure of TGFbRI complexed with a pyrazolone inhibitor -

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Basic information

Entry
Database: PDB / ID: 3kcf
TitleCrystal structure of TGFbRI complexed with a pyrazolone inhibitor
ComponentsTGF-beta receptor type-1
KeywordsTRANSFERASE / KINASE / TGFBETARI / STRUCTURE-BASED DRUG DESIGN / PROTEIN-INHIBITOR COMPLEX / Aortic aneurysm / ATP-binding / Craniosynostosis / Disease mutation / Disulfide bond / Glycoprotein / Magnesium / Manganese / Membrane / Metal-binding / Nucleotide-binding / Phosphoprotein / Polymorphism / Receptor / Serine/threonine-protein kinase / Transmembrane
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 / trophoblast cell migration / angiogenesis involved in coronary vascular morphogenesis / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / positive regulation of mesenchymal stem cell proliferation / ventricular compact myocardium morphogenesis / positive regulation of extracellular matrix assembly / positive regulation of tight junction disassembly / cardiac epithelial to mesenchymal transition / mesenchymal cell differentiation / TGFBR3 regulates TGF-beta signaling / transforming growth factor beta receptor activity, type I / positive regulation of vasculature development / neuron fate commitment / activin receptor complex / activin receptor activity, type I / regulation of epithelial to mesenchymal transition / type II transforming growth factor beta receptor binding / pharyngeal system development / transmembrane receptor protein serine/threonine kinase activity / receptor protein serine/threonine kinase / activin binding / TGFBR1 LBD Mutants in Cancer / germ cell migration / filopodium assembly / coronary artery morphogenesis / embryonic cranial skeleton morphogenesis / activin receptor signaling pathway / ventricular trabecula myocardium morphogenesis / response to cholesterol / I-SMAD binding / transforming growth factor beta binding / collagen fibril organization / negative regulation of chondrocyte differentiation / lens development in camera-type eye / endothelial cell activation / anterior/posterior pattern specification / positive regulation of filopodium assembly / artery morphogenesis / skeletal system 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 / epithelial to mesenchymal transition / blastocyst development / regulation of protein ubiquitination / bicellular tight junction / cellular response to transforming growth factor beta stimulus / endothelial cell migration / positive regulation of epithelial to mesenchymal transition / 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 / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / skeletal system development / post-embryonic development / negative regulation of extrinsic apoptotic signaling pathway / kidney development / cell motility / wound healing / peptidyl-serine phosphorylation / cellular response to growth factor stimulus / male gonad development / UCH proteinases / nervous system development / 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 / protein kinase activity / receptor complex / endosome / regulation of cell cycle / Ub-specific processing proteases / intracellular signal transduction / cilium / positive regulation of cell migration / membrane raft / protein serine/threonine kinase activity / positive regulation of cell population proliferation / apoptotic process / ubiquitin protein ligase binding
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-JZO / PHOSPHATE ION / TGF-beta receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsBoriack-Sjodin, P.A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Pyrazolone based TGFbetaR1 kinase inhibitors.
Authors: Guckian, K. / Carter, M.B. / Lin, E.Y. / Choi, M. / Sun, L. / Boriack-Sjodin, P.A. / Chuaqui, C. / Lane, B. / Cheung, K. / Ling, L. / Lee, W.C.
History
DepositionOct 21, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 22, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Feb 21, 2024Group: 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
Revision 1.3Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: TGF-beta receptor type-1
B: TGF-beta receptor type-1
C: TGF-beta receptor type-1
D: TGF-beta receptor type-1
E: TGF-beta receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)197,64023
Polymers194,6035
Non-polymers3,03718
Water543
1
A: TGF-beta receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,5665
Polymers38,9211
Non-polymers6454
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: TGF-beta receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,5665
Polymers38,9211
Non-polymers6454
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: TGF-beta receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,3763
Polymers38,9211
Non-polymers4552
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: TGF-beta receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,5665
Polymers38,9211
Non-polymers6454
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
5
E: TGF-beta receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,5665
Polymers38,9211
Non-polymers6454
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)174.025, 249.076, 138.011
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein
TGF-beta receptor type-1 / Transforming growth factor-beta receptor type I / TGF-beta receptor type I / TGF-beta type I ...Transforming growth factor-beta receptor type I / TGF-beta receptor type I / TGF-beta type I receptor / TbetaR-I / TGFR-1 / Serine/threonine-protein kinase receptor R4 / SKR4 / Activin receptor-like kinase 5 / ALK-5


Mass: 38920.641 Da / Num. of mol.: 5 / Fragment: UNP residues 162-503, GS AND KINASE DOMAINS
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFBR1, TGFBRI / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P36897, receptor protein serine/threonine kinase
#2: Chemical
ChemComp-JZO / 4-[3-(methoxymethyl)phenyl]-1,2-dimethyl-5-quinoxalin-6-yl-1,2-dihydro-3H-pyrazol-3-one


Mass: 360.409 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C21H20N4O2
#3: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / 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: 3.84 Å3/Da / Density % sol: 67.99 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.4
Details: Sodium potassium phosphate, pH 7.4, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X25 / Wavelength: 1.1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 1, 2005 / Details: monochromator
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 2.8→50 Å / Num. all: 73727 / Num. obs: 73525 / % possible obs: 99.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 2 / Redundancy: 4.4 % / Biso Wilson estimate: 52.9 Å2 / Rmerge(I) obs: 0.097
Reflection shellResolution: 2.8→2.9 Å / Redundancy: 3.49 % / Rmerge(I) obs: 0.521 / Mean I/σ(I) obs: 2.15 / Num. unique all: 7240 / % possible all: 99.3

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Processing

Software
NameVersionClassification
CBASSdata collection
CNX2005refinement
HKL-2000data reduction
SCALEPACKdata scaling
CNX2005phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Structure of TGFbRI with different inhibitor

Resolution: 2.8→34.86 Å / Rfactor Rfree error: 0.005 / Data cutoff high absF: 3273596.81 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.278 3747 5.1 %RANDOM
Rwork0.235 ---
all0.237 73478 --
obs0.237 73478 99.6 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 41.4394 Å2 / ksol: 0.357103 e/Å3
Displacement parametersBiso mean: 52.4 Å2
Baniso -1Baniso -2Baniso -3
1--6.84 Å20 Å20 Å2
2--7.06 Å20 Å2
3----0.22 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.45 Å0.37 Å
Luzzati d res low-5 Å
Luzzati sigma a0.57 Å0.48 Å
Refinement stepCycle: LAST / Resolution: 2.8→34.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13094 0 200 3 13297
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.5
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d24
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.75
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.511.5
X-RAY DIFFRACTIONc_mcangle_it2.682
X-RAY DIFFRACTIONc_scbond_it1.942
X-RAY DIFFRACTIONc_scangle_it3.12.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 2.8→2.98 Å / Rfactor Rfree error: 0.016 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.395 620 5.2 %
Rwork0.342 11309 -
obs--97.6 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1MSI_CNX_TOPPAR:protein_rep.paramMSI_CNX_TOPPAR:protein.top
X-RAY DIFFRACTION2MSI_CNX_TOPPAR:ion.parambio16178.top
X-RAY DIFFRACTION3MSI_CNX_TOPPAR:water_rep.paramMSI_CNX_TOPPAR:water.top
X-RAY DIFFRACTION4bio16178.paramMSI_CNX_TOPPAR:ion.top

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