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- PDB-5usq: ALK-5 kinase inhibitor complex -

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Basic information

Entry
Database: PDB / ID: 5usq
TitleALK-5 kinase inhibitor complex
ComponentsTGF-beta receptor type-1
KeywordsTransferase/Transferase Inhibitor / TGF-beta receptor type I / Serine/threonine-protein kinase receptor R4 / Activin receptor-like kinase 5 / 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 / mesenchymal cell differentiation / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / TGFBR3 regulates TGF-beta signaling / positive regulation of vasculature development / activin receptor activity, type I / regulation of epithelial to mesenchymal transition / cardiac epithelial to mesenchymal transition / activin receptor complex / transforming growth factor beta receptor activity, type I / neuron fate commitment / positive regulation of extracellular matrix assembly / TGFBR1 LBD Mutants in Cancer / type II transforming growth factor beta receptor binding / angiogenesis involved in coronary vascular morphogenesis / receptor protein serine/threonine kinase / transmembrane receptor protein serine/threonine kinase activity / pharyngeal system development / activin binding / germ cell migration / coronary artery morphogenesis / activin receptor signaling pathway / embryonic cranial skeleton morphogenesis / ventricular trabecula myocardium morphogenesis / filopodium assembly / response to cholesterol / transforming growth factor beta binding / I-SMAD binding / negative regulation of chondrocyte differentiation / skeletal system morphogenesis / collagen fibril organization / endothelial cell activation / endothelial cell proliferation / lens development in camera-type eye / positive regulation of filopodium assembly / anterior/posterior pattern specification / artery morphogenesis / ventricular septum morphogenesis / roof of mouth development / negative regulation of endothelial cell proliferation / SMAD binding / TGF-beta receptor signaling activates SMADs / positive regulation of SMAD protein signal transduction / blastocyst development / regulation of protein ubiquitination / epithelial to mesenchymal transition / endothelial cell migration / bicellular tight junction / 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 / post-embryonic development / transforming growth factor beta receptor signaling pathway / Downregulation of TGF-beta receptor signaling / thymus development / kidney development / negative regulation of cell migration / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / skeletal system development / cell motility / negative regulation of extrinsic apoptotic signaling pathway / positive regulation of apoptotic signaling pathway / wound healing / cellular response to growth factor stimulus / male gonad development / UCH proteinases / heart development / nervous system development / peptidyl-serine phosphorylation / positive regulation of cell growth / regulation of gene expression / in utero embryonic development / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / regulation of cell cycle / protein kinase activity / intracellular signal transduction / Ub-specific processing proteases / endosome / positive regulation of cell migration / membrane raft / protein serine/threonine kinase activity / ubiquitin protein ligase binding / positive regulation of cell population proliferation / regulation of DNA-templated transcription / positive regulation of gene expression / apoptotic process
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-8LY / TGF-beta receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.55 Å
AuthorsDougan, D.R. / Lawson, J.D.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2017
Title: Design, synthesis and optimization of 7-substituted-pyrazolo[4,3-b]pyridine ALK5 (activin receptor-like kinase 5) inhibitors.
Authors: Sabat, M. / Wang, H. / Scorah, N. / Lawson, J.D. / Atienza, J. / Kamran, R. / Hixon, M.S. / Dougan, D.R.
History
DepositionFeb 13, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 12, 2017Provider: repository / Type: Initial release
Revision 1.1Apr 26, 2017Group: Database references
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Mar 6, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / refine_hist
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine_hist.d_res_low

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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)34,7022
Polymers34,2651
Non-polymers4371
Water1,874104
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.589, 78.330, 90.712
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: 34265.398 Da / Num. of mol.: 1 / Fragment: UNP residues 123-421
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFBR1, ALK5, SKR4 / Production host: unidentified baculovirus
References: UniProt: P36897, receptor protein serine/threonine kinase
#2: Chemical ChemComp-8LY / N-[2-(5-chloro-2-fluorophenyl)pyridin-4-yl]-2-[(piperidin-4-yl)methyl]-2H-pyrazolo[4,3-b]pyridin-7-amine


Mass: 436.912 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H22ClFN6
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 104 / 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: 2.16 Å3/Da / Density % sol: 42.95 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 9.2 / Details: 16 % PEG 8000 100mM CHES pH 9.2 / PH range: 9.0 -9.4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.9765 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 5, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9765 Å / Relative weight: 1
ReflectionResolution: 2.55→50 Å / Num. obs: 10064 / % possible obs: 98.8 % / Redundancy: 4.9 % / Rmerge(I) obs: 0.137 / Χ2: 1.021 / Net I/σ(I): 6.9 / Num. measured all: 49464
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsΧ2Diffraction-ID% possible all
2.55-2.592.90.4130.95187.6
2.59-2.643.40.4280.948193.5
2.64-2.693.90.4010.95197.2
2.69-2.754.40.4181.039198.2
2.75-2.814.70.3791.058199.2
2.81-2.875.10.3621.037199.8
2.87-2.945.20.321.048199.8
2.94-3.025.40.2780.991100
3.02-3.115.50.271.11100
3.11-3.215.40.2091.051199.8
3.21-3.335.40.181.0421100
3.33-3.465.30.1451.0251100
3.46-3.625.40.1181.021199.8
3.62-3.815.30.1021.002199.8
3.81-4.055.40.0931.0121100
4.05-4.365.20.0831.0211100
4.36-4.85.20.0820.9951100
4.8-5.495.20.0891.0121100
5.49-6.924.90.11.0421100
6.92-504.70.0520.979199.7

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Processing

Software
NameVersionClassification
HKL-2000data collection
HKL-2000data scaling
REFMAC5.8.0135refinement
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
DENZOdata reduction
SCALEPACKdata scaling
RefinementResolution: 2.55→45.35 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.904 / WRfactor Rfree: 0.2162 / WRfactor Rwork: 0.1675 / FOM work R set: 0.83 / SU B: 21.203 / SU ML: 0.229 / SU R Cruickshank DPI: 0.242 / SU Rfree: 0.3099 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.31 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2305 482 4.8 %RANDOM
Rwork0.1792 ---
obs0.1817 9545 98.77 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 86.7 Å2 / Biso mean: 28.686 Å2 / Biso min: 9.83 Å2
Baniso -1Baniso -2Baniso -3
1--1.47 Å20 Å2-0 Å2
2--0.32 Å20 Å2
3---1.15 Å2
Refinement stepCycle: final / Resolution: 2.55→45.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2404 0 31 104 2539
Biso mean--24.73 26.35 -
Num. residues----299
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0192496
X-RAY DIFFRACTIONr_bond_other_d0.0020.022379
X-RAY DIFFRACTIONr_angle_refined_deg1.1941.9553373
X-RAY DIFFRACTIONr_angle_other_deg0.89235455
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9155298
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.04822.931116
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.36815447
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.8881523
X-RAY DIFFRACTIONr_chiral_restr0.0650.2365
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.022789
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02592
LS refinement shellResolution: 2.551→2.617 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.299 36 -
Rwork0.24 628 -
all-664 -
obs--89.25 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.03130.1385-0.06061.036-0.13640.39130.0062-0.012-0.0178-0.0306-0.0221-0.01330.01910.06020.01590.0168-0.0053-0.01320.0323-0.01640.050912.432861.7153.3628
20.48270.16010.24140.49260.3320.50020.0181-0.02970.0955-0.0082-0.03280.0447-0.0052-0.02380.01470.01290.0089-0.01230.0108-0.02080.049911.326783.388516.1773
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A200 - 279
2X-RAY DIFFRACTION2A280 - 498

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