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- PDB-3h9r: Crystal structure of the kinase domain of type I activin receptor... -

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Basic information

Entry
Database: PDB / ID: 3h9r
TitleCrystal structure of the kinase domain of type I activin receptor (ACVR1) in complex with FKBP12 and dorsomorphin
Components
  • Activin receptor type-1
  • Peptidyl-prolyl cis-trans isomerase FKBP1A
KeywordsISOMERASE/PROTEIN KINASE / Structural Genomics / Structural Genomics Consortium / SGC / ATP-binding / Disease mutation / Glycoprotein / Kinase / Magnesium / Manganese / Membrane / Metal-binding / Nucleotide-binding / Phosphoprotein / Receptor / Serine/threonine-protein kinase / Transferase / Transmembrane / Isomerase / Rotamase / ISOMERASE-PROTEIN KINASE 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 / BMP receptor activity / endocardial cushion fusion / activin receptor binding / positive regulation of cardiac epithelial to mesenchymal transition ...endocardial cushion cell fate commitment / mitral valve morphogenesis / BMP receptor complex / macrolide binding / cardiac muscle cell fate commitment / atrial septum primum morphogenesis / BMP receptor activity / endocardial cushion fusion / activin receptor binding / positive regulation of cardiac epithelial to mesenchymal transition / acute inflammatory response / positive regulation of determination of dorsal identity / transforming growth factor beta receptor activity, type I / 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 / activin receptor activity, type I / endocardial cushion formation / receptor protein serine/threonine kinase / transmembrane receptor protein serine/threonine kinase activity / pharyngeal system development / TGFBR1 LBD Mutants in Cancer / 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 / regulation of amyloid precursor protein catabolic process / terminal cisterna / ryanodine receptor complex / determination of left/right symmetry / signaling receptor inhibitor activity / 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 / peptide hormone binding / mTORC1-mediated signalling / regulation of ryanodine-sensitive calcium-release channel activity / positive regulation of intracellular signal transduction / mesoderm formation / Calcineurin activates NFAT / positive regulation of SMAD protein signal transduction / regulation of ossification / regulation of immune response / BMP signaling pathway / positive regulation of bone mineralization / positive regulation of osteoblast differentiation / negative regulation of signal transduction / heart morphogenesis / supramolecular fiber organization / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / sarcoplasmic reticulum membrane / transforming growth factor beta receptor signaling pathway / protein tyrosine kinase binding / T cell activation / protein maturation / sarcoplasmic reticulum / negative regulation of extrinsic apoptotic signaling pathway / 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 / SARS-CoV-1 activates/modulates innate immune responses / Z disc / osteoblast differentiation / apical part of cell / 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-TAK / Peptidyl-prolyl cis-trans isomerase FKBP1A / Activin receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 Å
AuthorsChaikuad, A. / Alfano, I. / Shrestha, B. / Muniz, J.R.C. / Petrie, K. / Fedorov, O. / Phillips, C. / Bishop, S. / Mahajan, P. / Pike, A.C.W. ...Chaikuad, A. / Alfano, I. / Shrestha, B. / Muniz, J.R.C. / Petrie, K. / Fedorov, O. / Phillips, C. / Bishop, S. / Mahajan, P. / Pike, A.C.W. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Weigelt, J. / Bountra, C. / Knapp, S. / Bullock, A. / Structural Genomics Consortium (SGC)
CitationJournal: J.Biol.Chem. / Year: 2012
Title: Structure of the Bone Morphogenetic Protein Receptor ALK2 and Implications for Fibrodysplasia Ossificans Progressiva.
Authors: Chaikuad, A. / Alfano, I. / Kerr, G. / Sanvitale, C.E. / Boergermann, J.H. / Triffitt, J.T. / von Delft, F. / Knapp, S. / Knaus, P. / Bullock, A.N.
History
DepositionApr 30, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 2, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Nov 28, 2012Group: Database references
Revision 1.3Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _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

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)50,91611
Polymers49,4542
Non-polymers1,4629
Water4,738263
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3950 Å2
ΔGint-70 kcal/mol
Surface area19110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)43.349, 62.345, 171.597
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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


Mass: 37398.746 Da / Num. of mol.: 1 / Fragment: ACVR1 kinase domain (residue 172-499)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACVR1, ACVRLK2 / Plasmid: PFB-LIC-Bse / Production host: Baculovirus
References: UniProt: Q04771, receptor protein serine/threonine kinase
#2: Protein Peptidyl-prolyl cis-trans isomerase FKBP1A / PPIase FKBP1A / FK506-binding protein 1A / FKBP-1A / Rotamase / Immunophilin FKBP12 / 12 kDa FKBP / FKBP-12


Mass: 12054.782 Da / Num. of mol.: 1 / Fragment: FKBP12
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FKBP1, FKBP12, FKBP1A / Plasmid: pNIC28-BSA4 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)-R3 / References: UniProt: P62942, peptidylprolyl isomerase

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Non-polymers , 4 types, 272 molecules

#3: Chemical ChemComp-TAK / 6-[4-(2-piperidin-1-ylethoxy)phenyl]-3-pyridin-4-ylpyrazolo[1,5-a]pyrimidine / Dorsomorphin


Mass: 399.488 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H25N5O
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 263 / 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: 2.34 Å3/Da / Density % sol: 47.53 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 30% PEG 3350; 0.25M Ammonium sulphate; 0.1M Bis-Tris, pH 6.0, VAPOR DIFFUSION, SITTING DROP, temperature 277.15K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.905 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 15, 2009 / Details: Kirkpatrick Baez bimorph mirror pair
RadiationMonochromator: Si (111) double crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.905 Å / Relative weight: 1
ReflectionResolution: 2.35→42.15 Å / Num. all: 20182 / Num. obs: 20161 / % possible obs: 99.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 2 / Redundancy: 4.1 % / Biso Wilson estimate: 32.8 Å2 / Rmerge(I) obs: 0.16 / Net I/σ(I): 7.4
Reflection shellResolution: 2.35→2.48 Å / Redundancy: 4 % / Rmerge(I) obs: 0.684 / Mean I/σ(I) obs: 2 / Num. unique all: 2892 / % possible all: 100

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Processing

Software
NameVersionClassification
PHASERphasing
REFMAC5.5.0089refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1A7X CHAIN A, 1B6C CHAIN B

1a7x

1b6c


Resolution: 2.35→42.15 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.887 / SU B: 16.726 / SU ML: 0.187 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.407 / ESU R Free: 0.269 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25594 1025 5.1 %RANDOM
Rwork0.1866 ---
all0.1866 20088 --
obs0.19022 19063 99.53 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 11.256 Å2
Baniso -1Baniso -2Baniso -3
1-0.57 Å20 Å20 Å2
2---0.22 Å20 Å2
3----0.35 Å2
Refine analyzeLuzzati coordinate error obs: 0.291 Å
Refinement stepCycle: LAST / Resolution: 2.35→42.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3303 0 94 263 3660
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0223464
X-RAY DIFFRACTIONr_bond_other_d0.0010.022385
X-RAY DIFFRACTIONr_angle_refined_deg1.4691.984677
X-RAY DIFFRACTIONr_angle_other_deg0.8943.0015771
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7815415
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.123.562146
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.18115590
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.8051523
X-RAY DIFFRACTIONr_chiral_restr0.0880.2513
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0213729
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02683
X-RAY DIFFRACTIONr_mcbond_it1.32232077
X-RAY DIFFRACTIONr_mcbond_other0.2173850
X-RAY DIFFRACTIONr_mcangle_it2.64563360
X-RAY DIFFRACTIONr_scbond_it5.32281387
X-RAY DIFFRACTIONr_scangle_it7.624111317
LS refinement shellResolution: 2.35→2.411 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.332 76 -
Rwork0.282 1393 -
obs--98.86 %
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)
15.46784.16722.63874.8968-0.027910.9362-0.0724-0.0336-0.27730.13920.09080.01350.18830.2607-0.01840.1178-0.01730.00140.09380.07460.108632.88258.3366176.8082
21.9626-0.3306-0.60091.7625-0.2892.3677-0.08150.0054-0.1675-0.01340.07320.15450.1771-0.14130.00820.0178-0.01790.00510.03380.01230.034622.23095.8893163.3551
31.29060.27340.82911.79540.18422.14630.03870.0999-0.0345-0.1102-0.0372-0.03130.09050.111-0.00150.01770.01140.01560.04140.00980.037429.5018.0785139.6688
42.7687-1.2078-0.13633.47860.04351.8395-0.0783-0.3093-0.04990.31840.1119-0.13560.1399-0.0021-0.03360.10650.0318-0.01070.15040.06620.102525.6974-4.7756184.416
51.8715-0.56171.72372.04431.80835.7725-0.1599-0.2433-0.01570.14130.010.07370.0883-0.10520.14990.121-0.01570.0270.11860.06490.150621.5506-8.1794181.3413
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A-1 - 189
2X-RAY DIFFRACTION2A190 - 290
3X-RAY DIFFRACTION3A291 - 499
4X-RAY DIFFRACTION4B2 - 57
5X-RAY DIFFRACTION5B58 - 108

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