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- PDB-4x0m: Selection of fragments for kinase inhibitor design: decoration is key -

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Basic information

Entry
Database: PDB / ID: 4x0m
TitleSelection of fragments for kinase inhibitor design: decoration is key
ComponentsTGF-beta receptor type-1
KeywordsTRANSFERASE / PROTEIN KINASE / INHIBITOR COMPLEX
Function / homology
Function and homology information


extracellular structure organization / epicardium morphogenesis / parathyroid gland development / transforming growth factor beta ligand-receptor complex / regulation of cardiac muscle cell proliferation / myofibroblast differentiation / positive regulation of tight junction disassembly / 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 / parathyroid gland development / transforming growth factor beta ligand-receptor complex / regulation of cardiac muscle cell proliferation / myofibroblast differentiation / positive regulation of tight junction disassembly / positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation / TGFBR2 Kinase Domain Mutants in Cancer / transforming growth factor beta receptor activity / positive regulation of mesenchymal stem cell proliferation / ventricular compact myocardium morphogenesis / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / positive regulation of vasculature development / regulation of epithelial to mesenchymal transition / activin receptor activity, type I / cardiac epithelial to mesenchymal transition / transforming growth factor beta receptor activity, type I / activin receptor complex / mesenchymal cell differentiation / neuron fate commitment / germ cell migration / positive regulation of extracellular matrix assembly / type II transforming growth factor beta receptor binding / TGFBR1 LBD Mutants in Cancer / angiogenesis involved in coronary vascular morphogenesis / receptor protein serine/threonine kinase / transmembrane receptor protein serine/threonine kinase activity / pharyngeal system development / activin binding / coronary artery morphogenesis / activin receptor signaling pathway / filopodium assembly / ventricular trabecula myocardium morphogenesis / transforming growth factor beta binding / embryonic cranial skeleton morphogenesis / response to cholesterol / I-SMAD binding / negative regulation of chondrocyte differentiation / collagen fibril organization / endothelial cell proliferation / endothelial cell activation / skeletal system morphogenesis / lens development in camera-type eye / positive regulation of filopodium assembly / anterior/posterior pattern specification / artery morphogenesis / ventricular septum morphogenesis / roof of mouth development / TGF-beta receptor signaling activates SMADs / SMAD binding / negative regulation of endothelial cell proliferation / positive regulation of SMAD protein signal transduction / blastocyst development / regulation of protein ubiquitination / endothelial cell migration / bicellular tight junction / epithelial to mesenchymal transition / positive regulation of epithelial to mesenchymal transition / positive regulation of apoptotic signaling pathway / positive regulation of stress fiber assembly / cellular response to transforming growth factor beta stimulus / positive regulation of endothelial cell proliferation / Downregulation of TGF-beta receptor signaling / post-embryonic development / transforming growth factor beta receptor signaling pathway / negative regulation of cell migration / thymus development / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / kidney development / skeletal system development / cell motility / negative regulation of extrinsic apoptotic signaling pathway / wound healing / cellular response to growth factor stimulus / male gonad development / UCH proteinases / nervous system development / heart development / positive regulation of cell growth / regulation of gene expression / peptidyl-serine phosphorylation / in utero embryonic development / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / regulation of cell cycle / Ub-specific processing proteases / endosome / protein kinase activity / intracellular signal transduction / positive regulation of cell migration / membrane raft / protein serine/threonine kinase activity / apoptotic process / ubiquitin protein ligase binding / positive regulation of cell population proliferation / positive regulation of gene expression / regulation of DNA-templated transcription / positive regulation of DNA-templated transcription
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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-aminopyrido[2,3-d]pyrimidin-5(8H)-one / TGF-beta receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.68 Å
AuthorsCzodrowski, P. / Hoelzemann, G. / Barnickel, G. / Greiner, H. / Musil, D.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Selection of fragments for kinase inhibitor design: decoration is key.
Authors: Czodrowski, P. / Holzemann, G. / Barnickel, G. / Greiner, H. / Musil, D.
History
DepositionNov 21, 2014Deposition site: RCSB / Processing site: PDBE
Revision 1.0Dec 24, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 21, 2015Group: Database references
Revision 1.2Jan 10, 2024Group: 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-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1403
Polymers34,8821
Non-polymers2582
Water3,117173
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area230 Å2
ΔGint-17 kcal/mol
Surface area14350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.990, 76.880, 89.590
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein TGF-beta receptor type-1 / TGFR-1 / Activin A receptor type II-like protein kinase of 53kD / Activin receptor-like kinase 5 / ...TGFR-1 / Activin A receptor type II-like protein kinase of 53kD / Activin receptor-like kinase 5 / ALK5 / Serine/threonine-protein kinase receptor R4 / SKR4 / TGF-beta type I receptor / Transforming growth factor-beta receptor type I / TbetaR-I


Mass: 34882.148 Da / Num. of mol.: 1 / Fragment: UNP residues 200-503
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFBR1, ALK5, SKR4 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P36897, receptor protein serine/threonine kinase
#2: Chemical ChemComp-3WA / 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one


Mass: 162.149 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H6N4O
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 173 / 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: 2.07 Å3/Da / Density % sol: 40.66 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1 M Tris-HCl, 240 mM Li2SO4, 24% PEG 4000, pH 7.5
PH range: 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 13, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.68→38.7 Å / Num. obs: 32312 / % possible obs: 95.3 % / Observed criterion σ(I): -3 / Redundancy: 3.2 % / Biso Wilson estimate: 12.85 Å2 / Rmerge F obs: 0.179 / Rmerge(I) obs: 0.185 / Rrim(I) all: 0.218 / Χ2: 1.247 / Net I/σ(I): 9.22 / Num. measured all: 102541
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Highest resolution (Å)Rmerge F obsRmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible all
1.68-1.780.3970.4294.213178537845460.51484.5
1.78-1.90.3650.4245.5115992508550210.598.7
1.9-2.050.2790.3677.1814979471746410.43198.4
2.05-2.250.1950.28914030438243200.32798.6
2.25-2.510.1620.22710.1612935397438900.26597.9
2.51-2.90.140.18911.4711069353934040.2296.2
2.9-3.550.10.12813.529077302028920.15195.8
3.55-50.0630.07816.787185238722610.09494.7
50.0490.06117.54096142213370.07394

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Processing

Software
NameVersionClassification
XSCALEdata scaling
BUSTER2.11.4refinement
PDB_EXTRACT3.15data extraction
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1vjy

1vjy


Resolution: 1.68→38.69 Å / Cor.coef. Fo:Fc: 0.9183 / Cor.coef. Fo:Fc free: 0.8827 / SU R Cruickshank DPI: 0.121 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.125 / SU Rfree Blow DPI: 0.128 / SU Rfree Cruickshank DPI: 0.126
RfactorNum. reflection% reflectionSelection details
Rfree0.2393 13989 47.64 %RANDOM
Rwork0.1839 15375 --
obs0.2098 29363 86.83 %-
Displacement parametersBiso max: 85.82 Å2 / Biso mean: 15.61 Å2 / Biso min: 3.34 Å2
Baniso -1Baniso -2Baniso -3
1-2.9072 Å20 Å20 Å2
2---2.0366 Å20 Å2
3----0.8707 Å2
Refine analyzeLuzzati coordinate error obs: 0.22 Å
Refinement stepCycle: final / Resolution: 1.68→38.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2429 0 17 173 2619
Biso mean--16.47 20.16 -
Num. residues----303
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetRestraint functionWeight
X-RAY DIFFRACTIONc_mcbond_it1.3261.5SINUSOIDAL2
X-RAY DIFFRACTIONc_scbond_it2.1332HARMONIC2
X-RAY DIFFRACTIONc_mcangle_it1.9352HARMONIC5
X-RAY DIFFRACTIONc_scangle_it2.9282.5HARMONIC20
LS refinement shellResolution: 1.68→1.74 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.3142 1032 52.6 %
Rwork0.1967 930 -
all0.2553 1962 -
obs--86.83 %
Refinement TLS params.Method: refined / Origin x: 12.052 Å / Origin y: 75.8878 Å / Origin z: 12.3086 Å
111213212223313233
T0.0182 Å20.0001 Å20.0052 Å2--0.0058 Å20.0018 Å2---0.1378 Å2
L0.297 °20.3171 °20.1794 °2-0.481 °20.522 °2--0.5836 °2
S-0.0015 Å °-0.0153 Å °0.0537 Å °-0.0316 Å °0.0002 Å °0.0356 Å °-0.044 Å °0.0011 Å °0.0013 Å °
Refinement TLS groupSelection details: { A|* }
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1protein_rep.param
X-RAY DIFFRACTION2adp.par
X-RAY DIFFRACTION3water_rep.param
X-RAY DIFFRACTION4ion.param
X-RAY DIFFRACTION5emd.par

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