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- PDB-9j9d: Crystal structure of ALK5 kinase domain in complex with inhibitor... -

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Basic information

Entry
Database: PDB / ID: 9j9d
TitleCrystal structure of ALK5 kinase domain in complex with inhibitor HM-279
ComponentsTGF-beta receptor type-1
KeywordsONCOPROTEIN / Protein kinase / Inhibitor complex
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 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. ...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 / 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
Similarity search - Domain/homology
: / TGF-beta receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.337 Å
AuthorsArai, M. / Hanada, M. / Taniguchi, H. / Ohmoto, H. / Naka, K. / Sawa, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery of HM-279, a Potent Inhibitor of ALK5 for Improving Therapeutic Efficacy of Cancer Immunotherapy.
Authors: Arai, M. / Hanada, M. / Taniguchi, H. / Nakajima, F. / Ohmoto, H. / Inoue, T. / Naka, K. / Sawa, M.
History
DepositionAug 22, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 2, 2025Provider: repository / Type: Initial release
Revision 1.1Apr 23, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)35,6536
Polymers34,9531
Non-polymers7005
Water4,053225
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area620 Å2
ΔGint9 kcal/mol
Surface area14170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.455, 75.677, 89.625
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 / 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: 34953.223 Da / Num. of mol.: 1
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-A1L30 / 2-((1-(but-2-yn-1-yl)-1H-pyrazol-4-yl)(cyclopropylmethyl)amino)-5-(4-(dimethylcarbamoyl)-1H-pyrrol-2-yl)thiazole-4-carboxamide


Mass: 451.545 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H25N7O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


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


Mass: 18.015 Da / Num. of mol.: 225 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.06 Å3/Da / Density % sol: 40.28 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 20-25% PEG8000, 0.2 M Na acetate, 0.1 M Tris-HCl pH8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL44XU / Wavelength: 0.9 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: May 25, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 1.337→50 Å / Num. obs: 66655 / % possible obs: 99.2 % / Redundancy: 3.52 % / CC1/2: 0.998 / Net I/σ(I): 12.6
Reflection shellResolution: 1.337→1.42 Å / Num. unique obs: 20131 / CC1/2: 0.727

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
XDSdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2WOU

2wou


Resolution: 1.337→44.813 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.949 / SU B: 0.883 / SU ML: 0.037 / Cross valid method: FREE R-VALUE / ESU R: 0.059 / ESU R Free: 0.059
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2089 3290 5.001 %
Rwork0.1903 62495 -
all0.191 --
obs-65785 99.516 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 12.503 Å2
Baniso -1Baniso -2Baniso -3
1-0.001 Å20 Å2-0 Å2
2--0.003 Å2-0 Å2
3----0.004 Å2
Refinement stepCycle: LAST / Resolution: 1.337→44.813 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2351 0 48 225 2624
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0132539
X-RAY DIFFRACTIONr_bond_other_d0.0030.0172412
X-RAY DIFFRACTIONr_angle_refined_deg1.2031.6473443
X-RAY DIFFRACTIONr_angle_other_deg1.2241.5835540
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6265319
X-RAY DIFFRACTIONr_dihedral_angle_2_deg28.31120.685146
X-RAY DIFFRACTIONr_dihedral_angle_other_2_deg0.012101
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.7715448
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.3521524
X-RAY DIFFRACTIONr_chiral_restr0.0530.2325
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.022878
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02621
X-RAY DIFFRACTIONr_nbd_refined0.1930.2438
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1680.22127
X-RAY DIFFRACTIONr_nbtor_refined0.1540.21193
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0780.2983
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.0950.2164
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1290.212
X-RAY DIFFRACTIONr_nbd_other0.1450.254
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1320.218
X-RAY DIFFRACTIONr_mcbond_it0.5831.271207
X-RAY DIFFRACTIONr_mcbond_other0.5831.2691206
X-RAY DIFFRACTIONr_mcangle_it1.0541.8981510
X-RAY DIFFRACTIONr_mcangle_other1.0531.8991511
X-RAY DIFFRACTIONr_scbond_it0.6341.3161332
X-RAY DIFFRACTIONr_scbond_other0.6341.3171333
X-RAY DIFFRACTIONr_scangle_it1.0461.9431917
X-RAY DIFFRACTIONr_scangle_other1.0461.9441918
X-RAY DIFFRACTIONr_lrange_it2.68414.542892
X-RAY DIFFRACTIONr_lrange_other2.60314.3392861
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
1.337-1.3720.2572360.25244830.25248430.8780.8897.43960.231
1.372-1.4090.2412330.22344300.22446720.9070.91299.80740.203
1.409-1.450.2092270.21343070.21345650.9350.92899.32090.192
1.45-1.4950.2172220.20542110.20644490.9350.9499.64040.183
1.495-1.5430.2172160.19641070.19743310.9360.94399.81530.175
1.543-1.5980.1872080.1939510.1941620.9510.94999.92790.168
1.598-1.6580.1922010.19538260.19540370.9460.94699.75230.175
1.658-1.7250.1831940.19536810.19538970.9550.9599.43550.175
1.725-1.8020.2211870.19335480.19537360.9360.94599.97320.176
1.802-1.890.2131780.19233800.19435750.9490.9599.52450.178
1.89-1.9920.2251710.19232530.19434240.9360.9471000.181
1.992-2.1120.1971620.17530770.17732390.9540.9611000.172
2.112-2.2580.1951520.17228890.17330430.9580.95999.93430.172
2.258-2.4380.2031420.18526960.18628390.9490.95499.96480.191
2.438-2.670.211310.18625030.18726370.9460.95399.88620.197
2.67-2.9840.2161200.18822670.1923930.9440.95199.74930.205
2.984-3.4430.2041050.17520080.17721380.9520.9698.83070.199
3.443-4.2110.172900.17217040.17218150.970.96798.8430.2
4.211-5.9290.223720.18613670.18714450.9590.96899.58480.231
5.929-44.8130.285430.2418070.2438640.9370.94198.37960.291

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