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- PDB-6i1s: Crystal structure of the ACVR1 (ALK2) kinase in complex with FKBP... -

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Basic information

Entry
Database: PDB / ID: 6i1s
TitleCrystal structure of the ACVR1 (ALK2) kinase in complex with FKBP12 and the inhibitor E6201
Components
  • Activin receptor type-1
  • Peptidyl-prolyl cis-trans isomerase FKBP1A
KeywordsSIGNALING PROTEIN / Kinase / Inhibitor / ALK2 / ACVR1 / FKBP12 / Complex
Function / homology
Function and homology information


endocardial cushion cell fate commitment / mitral valve morphogenesis / BMP receptor complex / macrolide binding / cardiac muscle cell fate commitment / atrial septum primum morphogenesis / endocardial cushion fusion / activin receptor binding / positive regulation of cardiac epithelial to mesenchymal transition / acute inflammatory response ...endocardial cushion cell fate commitment / mitral valve morphogenesis / BMP receptor complex / macrolide binding / cardiac muscle cell fate commitment / atrial septum primum morphogenesis / endocardial cushion fusion / activin receptor binding / positive regulation of cardiac epithelial to mesenchymal transition / acute inflammatory response / positive regulation of determination of dorsal identity / smooth muscle cell differentiation / regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion / cytoplasmic side of membrane / activin receptor complex / transforming growth factor beta receptor binding / endocardial cushion formation / transforming growth factor beta receptor activity, type I / activin receptor activity, type II / BMP receptor activity / activin receptor activity, type I / 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 / cellular response to BMP stimulus / type I transforming growth factor beta receptor binding / negative regulation of activin receptor signaling pathway / activin receptor signaling pathway / heart trabecula formation / embryonic heart tube morphogenesis / gastrulation with mouth forming second / I-SMAD binding / dorsal/ventral pattern formation / transforming growth factor beta binding / signaling receptor inhibitor activity / regulation of amyloid precursor protein catabolic process / terminal cisterna / ryanodine receptor complex / determination of left/right symmetry / neural crest cell migration / atrioventricular valve morphogenesis / 'de novo' protein folding / ventricular cardiac muscle tissue morphogenesis / branching involved in blood vessel morphogenesis / ventricular septum morphogenesis / FK506 binding / negative regulation of G1/S transition of mitotic cell cycle / SMAD binding / germ cell development / TGF-beta receptor signaling activates SMADs / positive regulation of intracellular signal transduction / mTORC1-mediated signalling / peptide hormone binding / mesoderm formation / Calcineurin activates NFAT / regulation of ryanodine-sensitive calcium-release channel activity / positive regulation of SMAD protein signal transduction / regulation of ossification / BMP signaling pathway / regulation of immune response / positive regulation of bone mineralization / positive regulation of osteoblast differentiation / negative regulation of signal transduction / heart morphogenesis / supramolecular fiber organization / sarcoplasmic reticulum membrane / calcium channel regulator activity / transforming growth factor beta receptor signaling pathway / protein maturation / T cell activation / protein tyrosine kinase binding / sarcoplasmic reticulum / peptidyl-prolyl cis-trans isomerase activity / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / RNA polymerase II CTD heptapeptide repeat P3 isomerase activity / RNA polymerase II CTD heptapeptide repeat P6 isomerase activity / negative regulation of extrinsic apoptotic signaling pathway / peptidylprolyl isomerase / negative regulation of transforming growth factor beta receptor signaling pathway / cellular response to growth factor stimulus / Z disc / osteoblast differentiation / SARS-CoV-1 activates/modulates innate immune responses / apical part of cell / protein folding / regulation of protein localization / heart development / protein refolding / in utero embryonic development / amyloid fibril formation / Potential therapeutics for SARS / transmembrane transporter binding / positive regulation of canonical NF-kappaB signal transduction / cell differentiation / protein kinase activity / positive regulation of cell migration
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 / Chitinase A; domain 3 - #40 / : / Snake toxin-like superfamily ...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 / Chitinase A; domain 3 - #40 / : / Snake toxin-like superfamily / Chitinase A; domain 3 / FKBP-type peptidyl-prolyl cis-trans isomerase / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / Peptidyl-prolyl cis-trans isomerase domain superfamily / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Roll / 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-E26 / Peptidyl-prolyl cis-trans isomerase FKBP1A / Activin receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.52 Å
AuthorsWilliams, E.P. / Pinkas, D.M. / Fortin, J. / Newman, J.A. / Bradshaw, W.J. / Mahajan, P. / Kupinska, K. / Burgess-Brown, N. / von Delft, F. / Arrowsmith, C.H. ...Williams, E.P. / Pinkas, D.M. / Fortin, J. / Newman, J.A. / Bradshaw, W.J. / Mahajan, P. / Kupinska, K. / Burgess-Brown, N. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Bullock, A.N.
CitationJournal: Cancer Cell / Year: 2020
Title: Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas.
Authors: Fortin, J. / Tian, R. / Zarrabi, I. / Hill, G. / Williams, E. / Sanchez-Duffhues, G. / Thorikay, M. / Ramachandran, P. / Siddaway, R. / Wong, J.F. / Wu, A. / Apuzzo, L.N. / Haight, J. / You- ...Authors: Fortin, J. / Tian, R. / Zarrabi, I. / Hill, G. / Williams, E. / Sanchez-Duffhues, G. / Thorikay, M. / Ramachandran, P. / Siddaway, R. / Wong, J.F. / Wu, A. / Apuzzo, L.N. / Haight, J. / You-Ten, A. / Snow, B.E. / Wakeham, A. / Goldhamer, D.J. / Schramek, D. / Bullock, A.N. / Dijke, P.T. / Hawkins, C. / Mak, T.W.
History
DepositionOct 30, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 11, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 25, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 24, 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: Activin receptor type-1
B: Peptidyl-prolyl cis-trans isomerase FKBP1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,47012
Polymers49,4542
Non-polymers1,01610
Water4,270237
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Each protein was individually verified by intact Mass Spec and the complex was purified by gel filtration and analysed by SDS PAGE. Comparison to single protein elution ...Evidence: gel filtration, Each protein was individually verified by intact Mass Spec and the complex was purified by gel filtration and analysed by SDS PAGE. Comparison to single protein elution profiles showed a peak shift in the gel filtration profile that confirms complex formation.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3580 Å2
ΔGint-20 kcal/mol
Surface area19000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.309, 108.599, 114.389
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Activin receptor type-1 / Activin receptor type I / ACTR-I / Activin receptor-like kinase 2 / ALK-2 / Serine/threonine- ...Activin receptor type I / ACTR-I / Activin receptor-like kinase 2 / ALK-2 / Serine/threonine-protein kinase receptor R1 / SKR1 / TGF-B superfamily receptor type I / TSR-I


Mass: 37398.746 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Standard peptide protein chain. / Source: (gene. exp.) Homo sapiens (human) / Gene: ACVR1, ACVRLK2 / Production host: Spodoptera frugiperda (fall armyworm) / Variant (production host): Sf9
References: UniProt: Q04771, receptor protein serine/threonine kinase
#2: Protein Peptidyl-prolyl cis-trans isomerase FKBP1A / PPIase FKBP1A / 12 kDa FK506-binding protein / FKBP-12 / Calstabin-1 / FK506-binding protein 1A / ...PPIase FKBP1A / 12 kDa FK506-binding protein / FKBP-12 / Calstabin-1 / FK506-binding protein 1A / FKBP-1A / Immunophilin FKBP12 / Rotamase


Mass: 12054.782 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Standard polypetide protein chain. / Source: (gene. exp.) Homo sapiens (human) / Gene: FKBP1A, FKBP1, FKBP12 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P62942, peptidylprolyl isomerase

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Non-polymers , 4 types, 247 molecules

#3: Chemical ChemComp-E26 / (4~{S},5~{R},6~{Z},9~{S},10~{S},12~{E})-16-(ethylamino)-4,5-dimethyl-9,10,18-tris(oxidanyl)-3-oxabicyclo[12.4.0]octadeca-1(14),6,12,15,17-pentaene-2,8-dione


Mass: 389.442 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H27NO6 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 237 / 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: 2.79 Å3/Da / Density % sol: 55.88 % / Description: Clear crystal. Oblong.
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.05M ammonium sulfate, 30% pentaerythritol ethoxylate 15/4, 0.1M bis-tris pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: May 4, 2018
RadiationMonochromator: Double Crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.52→41.32 Å / Num. obs: 85856 / % possible obs: 100 % / Observed criterion σ(F): 2 / Redundancy: 5.8 % / Biso Wilson estimate: 15.41 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.074 / Rpim(I) all: 0.05 / Rrim(I) all: 0.089 / Net I/σ(I): 11.5
Reflection shellResolution: 1.52→1.55 Å / Redundancy: 5.8 % / Rmerge(I) obs: 0.98 / Mean I/σ(I) obs: 2 / Num. unique obs: 4196 / CC1/2: 0.635 / Rpim(I) all: 0.665 / Rrim(I) all: 1.19 / Χ2: 0.83 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX1.13-2998refinement
iMOSFLM7.2.2data reduction
Aimless7.0.044data scaling
PHASER7.0.044phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3H9R

3h9r


Resolution: 1.52→41.31 Å / Cross valid method: FREE R-VALUE / σ(F): 2
RfactorNum. reflection% reflectionSelection details
Rfree0.1927 4149 4.89 %Random selection
Rwork0.1767 ---
obs0.1775 85764 99.96 %-
Solvent computationVDW probe radii: 1.11 Å
Displacement parametersBiso mean: 17.43 Å2
Refinement stepCycle: LAST / Resolution: 1.52→41.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3363 0 66 237 3666

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