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- PDB-4x2f: Selection of fragments for kinase inhibitor design: decoration is key -

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Basic information

Entry
Database: PDB / ID: 4x2f
TitleSelection of fragments for kinase inhibitor design: decoration is key
ComponentsTGF-beta receptor type-1
KeywordsTransferase/Transferase Inhibitor / TRANSFERASE / PROTEIN KINASE / INHIBITOR COMPLEX / Transferase-Transferase 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
Chem-3WJ / TGF-beta receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.49 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 26, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 28, 2015Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)35,2313
Polymers34,8821
Non-polymers3492
Water4,738263
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area230 Å2
ΔGint-16 kcal/mol
Surface area14420 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.250, 77.530, 89.850
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-3WJ / 4-amino-8-(4-aminophenyl)pyrido[2,3-d]pyrimidin-5(8H)-one


Mass: 253.259 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H11N5O
#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.: 263 / 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: 2.11 Å3/Da / Density % sol: 41.69 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
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: PSI 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: 1.49→17.2 Å / Num. obs: 48030 / % possible obs: 98.5 % / Redundancy: 7 % / Net I/σ(I): 19.8

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Processing

Software
NameVersionClassification
BUSTER-TNTBUSTER 2.11.5refinement
PDB_EXTRACT3.15data extraction
XDSdata reduction
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.49→21.82 Å / Cor.coef. Fo:Fc: 0.9581 / Cor.coef. Fo:Fc free: 0.9376 / SU R Cruickshank DPI: 0.067 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.07 / SU Rfree Blow DPI: 0.071 / SU Rfree Cruickshank DPI: 0.069
RfactorNum. reflection% reflectionSelection details
Rfree0.1911 2401 5 %RANDOM
Rwork0.1632 ---
obs0.1646 48011 97.92 %-
Displacement parametersBiso max: 86.16 Å2 / Biso mean: 19.2 Å2 / Biso min: 7.16 Å2
Baniso -1Baniso -2Baniso -3
1-1.3276 Å20 Å20 Å2
2---2.1998 Å20 Å2
3---0.8722 Å2
Refine analyzeLuzzati coordinate error obs: 0.158 Å
Refinement stepCycle: final / Resolution: 1.49→21.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2430 0 24 263 2717
Biso mean--18.54 27.86 -
Num. residues----303
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d918SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes61HARMONIC2
X-RAY DIFFRACTIONt_gen_planes380HARMONIC5
X-RAY DIFFRACTIONt_it2558HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion328SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3292SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2558HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3467HARMONIC20.99
X-RAY DIFFRACTIONt_omega_torsion3.93
X-RAY DIFFRACTIONt_other_torsion13.85
LS refinement shellResolution: 1.49→1.53 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2107 130 4.98 %
Rwork0.2132 2478 -
all0.213 2608 -
obs--97.92 %
Refinement TLS params.Method: refined / Origin x: 12.0042 Å / Origin y: 76.3805 Å / Origin z: 12.1617 Å
111213212223313233
T-0.0297 Å2-0.0021 Å2-0.0007 Å2--0.0156 Å20.0016 Å2---0.0258 Å2
L0.2703 °20.1596 °20.1539 °2-0.45 °20.382 °2--0.6388 °2
S-0.0259 Å °-0.0084 Å °0.0448 Å °-0.0431 Å °0.0021 Å °0.0329 Å °-0.0826 Å °0.0077 Å °0.0238 Å °
Refinement TLS groupSelection details: { A|* }

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