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- PDB-5fri: ALK5 in complex witha an N-(4-anilino-2-pyridyl)acetamide inhibitor. -

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Basic information

Entry
Database: PDB / ID: 5fri
TitleALK5 in complex witha an N-(4-anilino-2-pyridyl)acetamide inhibitor.
ComponentsTGF-BETA RECEPTOR TYPE-1
KeywordsTRANSFERASE
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-ZUQ / TGF-beta receptor type-1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsGoldberg, F.W. / Daunt, P. / Pearson, S.E. / Greenwood, R. / Debreczeni, J. / Grist, M.
CitationJournal: Med. Chem. Commun. / Year: 2016
Title: Identification and optimisation of a series of N-(4-anilino-2-pyridyl)acetamide activin receptor-like kinase 1 (ALK1) inhibitors
Authors: Goldberg, F.W. / Daunt, P. / Pearson, S.E. / Greenwood, R. / Debreczeni, J. / Grist, M.
History
DepositionDec 17, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 27, 2016Provider: repository / Type: Initial release
Revision 1.1May 16, 2018Group: Data collection / Database references / Category: citation / diffrn_source
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _diffrn_source.pdbx_synchrotron_beamline
Revision 1.2May 8, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.method
Revision 1.3May 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)34,8364
Polymers34,3801
Non-polymers4573
Water4,342241
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.960, 76.700, 89.070
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 / TGFR-1 / ALK5 / ACTIVIN A RECEPTOR TYPE II-LIKE PROTEIN KINASE OF 53KD / ACTIVIN RECEPTOR-LIKE ...TGFR-1 / ALK5 / ACTIVIN A RECEPTOR TYPE II-LIKE PROTEIN KINASE OF 53KD / ACTIVIN RECEPTOR-LIKE KINASE 5 / ALK-5 / ALK5 / SERINE/THREONINE-PROTEIN KINASE RECEPTOR R4 / SKR4 / TGF-BETA TYPE I RECEPTOR / TRANSFORMING GROWTH FACTOR-BETA RECEPTOR TYPE I / TGF-BETA RECEPTOR TYPE I / TBETAR-I


Mass: 34379.504 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 200-498
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli)
References: UniProt: P36897, receptor protein serine/threonine kinase
#2: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-ZUQ / N-[4-[(6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-yl)amino]-2-pyridyl]cyclopropanecarboxamide


Mass: 332.742 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H13ClN4O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 241 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.08 Å3/Da / Density % sol: 40.99 % / 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: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Type: ESRF / Wavelength: 0.98
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.8→58.12 Å / Num. obs: 19007 / % possible obs: 94.2 % / Observed criterion σ(I): 2 / Redundancy: 5 % / Rmerge(I) obs: 0.04 / Net I/σ(I): 11.5
Reflection shellResolution: 1.8→1.9 Å / % possible all: 70.7

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Processing

Software
NameVersionClassification
REFMAC5.5.0102refinement
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→20 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.939 / SU B: 6.74 / SU ML: 0.09 / Cross valid method: THROUGHOUT / ESU R: 0.18 / ESU R Free: 0.14 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.19345 1034 5.2 %RANDOM
Rwork0.16189 ---
obs0.16356 19007 99.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 19.132 Å2
Baniso -1Baniso -2Baniso -3
1--0.48 Å20 Å20 Å2
2--1.29 Å20 Å2
3----0.81 Å2
Refinement stepCycle: LAST / Resolution: 2→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2396 0 31 241 2668
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.022497
X-RAY DIFFRACTIONr_bond_other_d0.0010.021734
X-RAY DIFFRACTIONr_angle_refined_deg1.1791.943374
X-RAY DIFFRACTIONr_angle_other_deg0.8234185
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8325304
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.2822.75116
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.77115439
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.8251524
X-RAY DIFFRACTIONr_chiral_restr0.0740.2363
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.022805
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02538
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.90221497
X-RAY DIFFRACTIONr_mcbond_other0.1682616
X-RAY DIFFRACTIONr_mcangle_it1.5632409
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.99321000
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it1.613960
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: 2→2.051 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2 73 -
Rwork0.179 1346 -
obs--99.3 %
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)
10.7848-0.4590.34941.0192-0.20310.52950.0276-0.02080.0318-0.0466-0.0276-0.03310.0178-0.038200.0088-0.00440.01140.0570.01380.02568.613115.69722.8587
20.86190.1954-0.21560.5018-0.46241.3083-0.0356-0.0501-0.064-0.0049-0.012-0.03830.12380.02020.04750.02710.00540.01250.00840.01590.03449.2806-4.953416.7222
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A198 - 284
2X-RAY DIFFRACTION2A285 - 498

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