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- PDB-2wot: ALK5 IN COMPLEX WITH 4-((5,6-dimethyl-2-(2-pyridyl)-3-pyridyl)oxy... -

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Entry
Database: PDB / ID: 2wot
TitleALK5 IN COMPLEX WITH 4-((5,6-dimethyl-2-(2-pyridyl)-3-pyridyl)oxy)-N-(3,4,5-trimethoxyphenyl)pyridin-2-amine
ComponentsTGF-BETA RECEPTOR TYPE-1
KeywordsTRANSFERASE / ALK5 / KINASE / MEMBRANE / RECEPTOR / MANGANESE / SERINE/THREONINE-PROTEIN KINASE / KINASE INHIBITOR / DISEASE MUTATION / CRANIOSYNOSTOSIS / NUCLEOTIDE-BINDING / TGF BETA TYPE I RECEPTOR / PHOSPHOPROTEIN / DISULFIDE BOND / AORTIC ANEURYSM / GLYCOPROTEIN / METAL-BINDING / TRANSMEMBRANE / ATP-BINDING
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-ZZG / TGF-beta receptor type-1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsNorman, R.A. / Debreczeni, J.E. / Goldberg, F.W. / Ward, R.A. / Finlay, R. / Powell, S.J. / Roberts, N.J. / Dishington, A.P. / Gingell, H.J. / Wickson, K.F. / Roberts, A.L.
CitationJournal: J.Med.Chem. / Year: 2009
Title: Rapid Generation of a High Quality Lead for Transforming Growth Factor-Beta (Tgf-Beta) Type I Receptor (Alk5).
Authors: Goldberg, F.W. / Ward, R.A. / Powell, S.J. / Debreczeni, J.E. / Norman, R.A. / Roberts, N.J. / Dishington, A.P. / Gingell, H.J. / Wickson, K.F. / Roberts, A.L.
History
DepositionJul 28, 2009Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 22, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Nov 23, 2011Group: Database references / Structure summary
Revision 1.3Nov 19, 2014Group: Data collection
Revision 1.4Apr 4, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.5May 8, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.method
Revision 1.6May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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

Downloads & links

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Assembly

Deposited unit
A: TGF-BETA RECEPTOR TYPE-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4603
Polymers34,9391
Non-polymers5212
Water5,495305
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.933, 78.218, 89.074
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-1 / ALK5 / TRANSFORMING GROWTH FACTOR-BETA RECEPTOR TYPE I / TGF-BETA RECEPTOR TYPE I / TGF-BETA TYPE I ...ALK5 / 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: 34939.199 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN, RESIDUES 200-503
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, receptor protein serine/threonine kinase
#2: Chemical ChemComp-ZZG / 4-[(5,6-DIMETHYL-2,2'-BIPYRIDIN-3-YL)OXY]-N-(3,4,5-TRIMETHOXYPHENYL)PYRIDIN-2-AMINE


Mass: 458.509 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H26N4O4
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 305 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsG198 AND G199 ARE CLONING ARTIFACTS.

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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: 2.03 Å3/Da / Density % sol: 39.36 % / Description: NONE
Crystal growMethod: vapor diffusion, sitting drop
Details: SITTING DROP METHOD. DROPS PROTEIN-PRECIPITANT 1-1, PROTEIN: 10MG/ML ALK5, PRECIPITANT: 20-30% PEG8K, 100 MM PCTP BUFFER PH 8.5-9.2, 0.2 M NAAC

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E / Wavelength: 1.5418
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Dec 24, 2006 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.85→22.5 Å / Num. obs: 25080 / % possible obs: 97.8 % / Observed criterion σ(I): 2 / Redundancy: 3.53 % / Biso Wilson estimate: 11.289 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 7.9
Reflection shellResolution: 1.85→1.95 Å / Redundancy: 1.94 % / Rmerge(I) obs: 0.37 / Mean I/σ(I) obs: 1.98 / % possible all: 87.9

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→22.27 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.92 / SU B: 7.013 / SU ML: 0.095 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.156 / ESU R Free: 0.142 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.22134 1281 5.1 %RANDOM
Rwork0.17883 ---
obs0.18098 23799 97.56 %-
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: 15.258 Å2
Baniso -1Baniso -2Baniso -3
1--0.14 Å20 Å20 Å2
2--0.12 Å20 Å2
3---0.03 Å2
Refinement stepCycle: LAST / Resolution: 1.85→22.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2400 0 38 305 2743
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0212489
X-RAY DIFFRACTIONr_bond_other_d0.0020.021669
X-RAY DIFFRACTIONr_angle_refined_deg1.11.9563371
X-RAY DIFFRACTIONr_angle_other_deg0.82934050
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6925306
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.323.393112
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.24315429
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5091519
X-RAY DIFFRACTIONr_chiral_restr0.0650.2364
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.022774
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02512
X-RAY DIFFRACTIONr_nbd_refined0.2030.2500
X-RAY DIFFRACTIONr_nbd_other0.1960.21750
X-RAY DIFFRACTIONr_nbtor_refined0.180.21234
X-RAY DIFFRACTIONr_nbtor_other0.0830.21237
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1330.2187
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.130.218
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2620.245
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1130.229
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.471.51573
X-RAY DIFFRACTIONr_mcbond_other0.0851.5621
X-RAY DIFFRACTIONr_mcangle_it0.76722422
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.21131105
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it1.8684.5947
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
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: 1.85→1.898 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.278 89 -
Rwork0.237 1440 -
obs--82.65 %
Refinement TLS params.Method: refined / Origin x: 9.0266 Å / Origin y: 1.4747 Å / Origin z: 12.5385 Å
111213212223313233
T-0.0356 Å20.002 Å20.0028 Å2--0.0202 Å2-0.0013 Å2---0.0297 Å2
L0.3491 °20.0637 °2-0.0825 °2-0.6322 °2-0.3499 °2--0.5347 °2
S-0.0144 Å °-0.0243 Å °-0.045 Å °-0.0086 Å °-0.0124 Å °-0.0292 Å °0.0463 Å °0.0005 Å °0.0267 Å °

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