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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 / cardiac muscle cell fate commitment / BMP receptor activity / endocardial cushion fusion / atrial septum primum morphogenesis / macrolide binding / positive regulation of cardiac epithelial to mesenchymal transition / activin receptor binding ...endocardial cushion cell fate commitment / mitral valve morphogenesis / BMP receptor complex / cardiac muscle cell fate commitment / BMP receptor activity / endocardial cushion fusion / atrial septum primum morphogenesis / macrolide binding / positive regulation of cardiac epithelial to mesenchymal transition / activin receptor binding / acute inflammatory response / positive regulation of determination of dorsal identity / transforming growth factor beta receptor activity, type I / smooth muscle cell differentiation / activin receptor complex / activin receptor activity, type I / endocardial cushion formation / regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion / transforming growth factor beta receptor binding / cytoplasmic side of membrane / pharyngeal system development / receptor protein serine/threonine kinase / transmembrane receptor protein serine/threonine kinase activity / activin binding / cellular response to BMP stimulus / TGFBR1 LBD Mutants in Cancer / type I transforming growth factor beta receptor binding / activin receptor signaling pathway / negative regulation of activin receptor signaling pathway / embryonic heart tube morphogenesis / heart trabecula formation / gastrulation with mouth forming second / I-SMAD binding / dorsal/ventral pattern formation / transforming growth factor beta binding / determination of left/right symmetry / regulation of amyloid precursor protein catabolic process / signaling receptor inhibitor activity / terminal cisterna / ryanodine receptor complex / atrioventricular valve morphogenesis / neural crest cell migration / 'de novo' protein folding / branching involved in blood vessel morphogenesis / ventricular cardiac muscle tissue morphogenesis / ventricular septum morphogenesis / negative regulation of G1/S transition of mitotic cell cycle / FK506 binding / SMAD binding / germ cell development / TGF-beta receptor signaling activates SMADs / peptide hormone binding / positive regulation of intracellular signal transduction / mesoderm formation / positive regulation of SMAD protein signal transduction / mTORC1-mediated signalling / regulation of ryanodine-sensitive calcium-release channel activity / regulation of ossification / Calcineurin activates NFAT / regulation of immune response / positive regulation of bone mineralization / positive regulation of osteoblast differentiation / BMP signaling pathway / negative regulation of signal transduction / heart morphogenesis / supramolecular fiber organization / sarcoplasmic reticulum membrane / transforming growth factor beta receptor signaling pathway / protein tyrosine kinase binding / T cell activation / sarcoplasmic reticulum / protein maturation / negative regulation of extrinsic apoptotic signaling pathway / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / calcium channel regulator activity / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / negative regulation of transforming growth factor beta receptor signaling pathway / cellular response to growth factor stimulus / Z disc / apical part of cell / SARS-CoV-1 activates/modulates innate immune responses / osteoblast differentiation / protein folding / regulation of protein localization / heart development / protein refolding / amyloid fibril formation / in utero embryonic development / Potential therapeutics for SARS / transmembrane transporter binding / cell differentiation / positive regulation of canonical NF-kappaB signal transduction / protein kinase activity / positive regulation of cell migration / cadherin binding / protein serine/threonine kinase activity / positive regulation of DNA-templated transcription / protein homodimerization activity / positive regulation of transcription by RNA polymerase II
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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