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- PDB-4c02: Crystal structure of human ACVR1 (ALK2) in complex with FKBP12.6 ... -

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Basic information

Entry
Database: PDB / ID: 4c02
TitleCrystal structure of human ACVR1 (ALK2) in complex with FKBP12.6 and dorsomorphin
Components
  • ACTIVIN RECEPTOR TYPE-1
  • PEPTIDYL-PROLYL CIS-TRANS ISOMERASE FKBP1B
KeywordsTRANSFERASE/ISOMERASE / TRANSFERASE-ISOMERASE COMPLEX / TRANSFERASE / DORSOMORPHIN
Function / homology
Function and homology information


endocardial cushion cell fate commitment / mitral valve morphogenesis / BMP receptor complex / endocardial cushion fusion / atrial septum primum morphogenesis / BMP receptor activity / cardiac muscle cell fate commitment / acute inflammatory response / activin receptor activity, type I / positive regulation of cardiac epithelial to mesenchymal transition ...endocardial cushion cell fate commitment / mitral valve morphogenesis / BMP receptor complex / endocardial cushion fusion / atrial septum primum morphogenesis / BMP receptor activity / cardiac muscle cell fate commitment / acute inflammatory response / activin receptor activity, type I / positive regulation of cardiac epithelial to mesenchymal transition / activin receptor complex / transforming growth factor beta receptor activity, type I / positive regulation of determination of dorsal identity / endocardial cushion formation / smooth muscle cell differentiation / receptor protein serine/threonine kinase / transmembrane receptor protein serine/threonine kinase activity / pharyngeal system development / activin binding / cellular response to BMP stimulus / activin receptor signaling pathway / negative regulation of activin receptor signaling pathway / positive regulation of sequestering of calcium ion / cyclic nucleotide binding / negative regulation of calcium-mediated signaling / embryonic heart tube morphogenesis / transforming growth factor beta binding / gastrulation with mouth forming second / negative regulation of insulin secretion involved in cellular response to glucose stimulus / dorsal/ventral pattern formation / negative regulation of release of sequestered calcium ion into cytosol / neuronal action potential propagation / determination of left/right symmetry / insulin secretion involved in cellular response to glucose stimulus / neural crest cell migration / atrioventricular valve morphogenesis / response to redox state / protein maturation by protein folding / 'de novo' protein folding / negative regulation of heart rate / negative regulation of G1/S transition of mitotic cell cycle / ventricular septum morphogenesis / branching involved in blood vessel morphogenesis / FK506 binding / positive regulation of axon regeneration / channel regulator activity / SMAD binding / germ cell development / positive regulation of SMAD protein signal transduction / peptide hormone binding / mesoderm formation / smooth muscle contraction / regulation of ossification / response to vitamin E / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / BMP signaling pathway / calcium channel inhibitor activity / positive regulation of osteoblast differentiation / positive regulation of bone mineralization / negative regulation of signal transduction / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / T cell proliferation / Ion homeostasis / release of sequestered calcium ion into cytosol / regulation of cytosolic calcium ion concentration / calcium channel complex / sarcoplasmic reticulum membrane / protein tyrosine kinase binding / transforming growth factor beta receptor signaling pathway / peptidylprolyl isomerase / negative regulation of extrinsic apoptotic signaling pathway / peptidyl-prolyl cis-trans isomerase activity / calcium-mediated signaling / response to hydrogen peroxide / cellular response to growth factor stimulus / Stimuli-sensing channels / Z disc / positive regulation of peptidyl-tyrosine phosphorylation / apical part of cell / heart development / positive regulation of cytosolic calcium ion concentration / protein refolding / in utero embryonic development / transmembrane transporter binding / protein kinase activity / positive regulation of cell migration / cadherin binding / signaling receptor binding / protein serine/threonine kinase activity / positive regulation of DNA-templated transcription / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / ATP binding / membrane / metal ion binding / plasma membrane / cytosol / cytoplasm
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 domain profile. / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase / Peptidyl-prolyl cis-trans isomerase domain superfamily / Protein tyrosine and serine/threonine kinase / 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 / 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
CITRATE ANION / Chem-TAK / Peptidyl-prolyl cis-trans isomerase FKBP1B / Activin receptor type-1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.17 Å
AuthorsWilliams, E. / Riesebos, E. / Vollmar, M. / Krojer, T. / Bradley, A. / Shrestha, L. / Kupinska, K. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. ...Williams, E. / Riesebos, E. / Vollmar, M. / Krojer, T. / Bradley, A. / Shrestha, L. / Kupinska, K. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Bullock, A.
CitationJournal: Ph D Thesis
Title: Crystal Structure of Human Acvr1 (Alk2) in Complex with Fkbp12.6 And Dorsomorphin
Authors: Williams, E. / Riesebos, E. / Vollmar, M. / Krojer, T. / Bradley, A. / Shrestha, L. / Kupinska, K. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Bullock, A.
History
DepositionJul 31, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 7, 2013Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2018Group: Database references / Category: citation_author / Item: _citation_author.name
Revision 2.0Feb 10, 2021Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Other / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / pdbx_database_status / pdbx_poly_seq_scheme / pdbx_struct_sheet_hbond / pdbx_unobs_or_zero_occ_atoms / pdbx_validate_torsion / struct_conf / struct_ref_seq / struct_sheet_range / struct_site / struct_site_gen
Item: _atom_site.auth_seq_id / _atom_site_anisotrop.pdbx_auth_seq_id ..._atom_site.auth_seq_id / _atom_site_anisotrop.pdbx_auth_seq_id / _pdbx_database_status.status_code_sf / _pdbx_poly_seq_scheme.pdb_seq_num / _pdbx_struct_sheet_hbond.range_1_auth_seq_id / _pdbx_struct_sheet_hbond.range_2_auth_seq_id / _pdbx_unobs_or_zero_occ_atoms.auth_seq_id / _pdbx_validate_torsion.auth_seq_id / _struct_conf.beg_auth_seq_id / _struct_conf.end_auth_seq_id / _struct_ref_seq.pdbx_auth_seq_align_beg / _struct_ref_seq.pdbx_auth_seq_align_end / _struct_sheet_range.beg_auth_seq_id / _struct_sheet_range.end_auth_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id / _struct_site_gen.auth_seq_id
Revision 2.1Dec 20, 2023Group: 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 FKBP1B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,91624
Polymers49,1972
Non-polymers2,71922
Water4,161231
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7250 Å2
ΔGint23.4 kcal/mol
Surface area18780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)182.330, 182.330, 182.330
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number213
Space group name H-MP4132

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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 KINA SE 2 / ALK-2 / SERINE/THREONINE- ...ACTIVIN RECEPTOR TYPE I / ACTR-I / ACTIVIN RECEPTOR-LIKE KINA SE 2 / ALK-2 / SERINE/THREONINE-PROTEIN KINASE RECEPTOR R1 / SKR1 / TG F-B SUPERFAMILY RECEPTOR TYPE I / TSR-I / ACVR1A


Mass: 37398.746 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 172-499
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFB-LIC-BSE / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / Strain (production host): SF9
References: UniProt: Q04771, non-specific protein-tyrosine kinase, receptor protein serine/threonine kinase
#2: Protein PEPTIDYL-PROLYL CIS-TRANS ISOMERASE FKBP1B / PPIASE FKBP1B / 12.6 KDA FK506-BINDING PROTEIN / 12.6 KDA FKB P / FKBP-12.6 / FK506-BINDING PROTEIN ...PPIASE FKBP1B / 12.6 KDA FK506-BINDING PROTEIN / 12.6 KDA FKB P / FKBP-12.6 / FK506-BINDING PROTEIN 1B / FKBP-1B / IMMUNOPHILIN FKBP 12.6 / ROTAMASE / H-FKBP-12 / FKBP1B


Mass: 11798.501 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PNIC28-BSA4 / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / Variant (production host): ROSETTA PLYSS / References: UniProt: P68106, peptidylprolyl isomerase

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Non-polymers , 4 types, 253 molecules

#3: Chemical
ChemComp-FLC / CITRATE ANION


Mass: 189.100 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C6H5O7
#4: 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
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 231 / Source method: isolated from a natural source / Formula: H2O

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Details

Sequence detailsN TERMINAL METHIONINE (RESIDUE 0) SEEN PRIOR TO RESIDUE 1 (GLY).

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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: 5.11 Å3/Da / Density % sol: 75.95 % / Description: NONE
Crystal growpH: 7.2 / Details: 1.8M AMMONIUM CITRATE, pH 7.2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9686
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 22, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9686 Å / Relative weight: 1
ReflectionResolution: 2.17→40 Å / Num. obs: 169113 / % possible obs: 99.9 % / Observed criterion σ(I): 2 / Redundancy: 9 % / Rmerge(I) obs: 0.17 / Net I/σ(I): 8
Reflection shellResolution: 2.17→2.23 Å / Redundancy: 9.3 % / Rmerge(I) obs: 1.07 / Mean I/σ(I) obs: 2 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.7.0032refinement
MOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRIES 1C9H AND 3H9R

1c9h

3h9r


Resolution: 2.17→39.82 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.949 / SU B: 6.385 / SU ML: 0.084 / Cross valid method: THROUGHOUT / ESU R: 0.125 / ESU R Free: 0.117 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.U VALUES WITH TLS ADDED DISORDERED REGIONS WERE NOT MODELED AND RELEVANT LOOPS DELETED FROM STRUCTURE.
RfactorNum. reflection% reflectionSelection details
Rfree0.19754 2787 5.1 %RANDOM
Rwork0.17729 ---
obs0.17833 52159 99.75 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 36.836 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 2.17→39.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3271 0 179 231 3681
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0193589
X-RAY DIFFRACTIONr_bond_other_d0.0010.023380
X-RAY DIFFRACTIONr_angle_refined_deg1.7671.9994865
X-RAY DIFFRACTIONr_angle_other_deg0.77737761
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3495442
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.91923.851148
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.79615583
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.4351522
X-RAY DIFFRACTIONr_chiral_restr0.1570.2538
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0214019
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02802
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_it4.7065.2371717
X-RAY DIFFRACTIONr_mcbond_other4.7075.2351716
X-RAY DIFFRACTIONr_mcangle_it6.5529.6792149
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it6.8386.3351872
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
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: 2.17→2.227 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3 194 -
Rwork0.276 3794 -
obs--99.97 %
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)
10.3214-0.0833-0.20060.16720.05910.5855-0.07070.00340.0361-0.01440.02240.0410.01060.08730.04830.0972-0.0132-0.00910.07960.01490.0353-50.99316.1065.1011
21.1255-0.0583-1.01881.4998-0.47631.1139-0.00930.07590.30580.06690.36480.23140.0013-0.1909-0.35550.04150.0350.02630.10430.08970.1408-82.681218.845321.2804
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A178 - 192
2X-RAY DIFFRACTION1A193 - 257
3X-RAY DIFFRACTION1A258 - 296
4X-RAY DIFFRACTION1A297 - 333
5X-RAY DIFFRACTION1A334 - 381
6X-RAY DIFFRACTION1A384 - 499
7X-RAY DIFFRACTION2B1 - 6
8X-RAY DIFFRACTION2B7 - 33
9X-RAY DIFFRACTION2B34 - 47
10X-RAY DIFFRACTION2B48 - 54
11X-RAY DIFFRACTION2B55 - 107

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