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- PDB-9mir: CryoEM structure of ALK3-ActRIIB bound to BMP6 -

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Basic information

Entry
Database: PDB / ID: 9mir
TitleCryoEM structure of ALK3-ActRIIB bound to BMP6
Components
  • ActRIIB
  • Bone Morphogenetic Protein 6 (BMP6)
  • receptor protein serine/threonine kinase
KeywordsSIGNALING PROTEIN / Signaling / Ligand / Complex / Receptor / Type I / Type II / TGFB / BMP
Function / homology
Function and homology information


neural plate mediolateral regionalization / paraxial mesoderm structural organization / positive regulation of cardiac ventricle development / fibrous ring of heart morphogenesis / positive regulation of transforming growth factor beta2 production / Mullerian duct regression / heart formation / atrioventricular node cell development / mesendoderm development / dorsal aorta morphogenesis ...neural plate mediolateral regionalization / paraxial mesoderm structural organization / positive regulation of cardiac ventricle development / fibrous ring of heart morphogenesis / positive regulation of transforming growth factor beta2 production / Mullerian duct regression / heart formation / atrioventricular node cell development / mesendoderm development / dorsal aorta morphogenesis / tricuspid valve morphogenesis / cardiac right ventricle morphogenesis / BMP binding / hindlimb morphogenesis / negative regulation of muscle cell differentiation / pharyngeal arch artery morphogenesis / regulation of lateral mesodermal cell fate specification / lateral mesoderm development / pituitary gland development / mitral valve morphogenesis / negative regulation of smooth muscle cell migration / BMP receptor activity / regulation of cellular senescence / ventricular compact myocardium morphogenesis / dorsal/ventral axis specification / neural crest cell development / transforming growth factor beta receptor activity, type I / ectoderm development / endocardial cushion formation / receptor protein serine/threonine kinase / ventricular trabecula myocardium morphogenesis / outflow tract septum morphogenesis / central nervous system neuron differentiation / positive regulation of mesenchymal cell proliferation / embryonic digit morphogenesis / ventricular septum morphogenesis / SMAD binding / odontogenesis of dentin-containing tooth / roof of mouth development / mesoderm formation / positive regulation of SMAD protein signal transduction / somatic stem cell population maintenance / developmental growth / chondrocyte differentiation / embryonic organ development / positive regulation of osteoblast differentiation / positive regulation of bone mineralization / somitogenesis / positive regulation of cardiac muscle cell proliferation / positive regulation of vascular associated smooth muscle cell proliferation / transforming growth factor beta receptor signaling pathway / lung development / epithelial cell proliferation / positive regulation of epithelial cell proliferation / caveola / negative regulation of neurogenesis / positive regulation of miRNA transcription / osteoblast differentiation / angiogenesis / in utero embryonic development / receptor complex / immune response / negative regulation of gene expression / external side of plasma membrane / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / ATP binding / 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 / 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
receptor protein serine/threonine kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsGoebel, E.J. / Saotome, K. / Franklin, M.C.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: CryoEM structure of ALK2:BMP6 reveals distinct mechanism that allow ALK2 to interact with both BMP and activin ligands.
Authors: Erich J Goebel / Senem Aykul / Warren W Hom / Kei Saotome / Aris N Economides / Matthew C Franklin / Vincent J Idone /
Abstract: Ligands in the transforming growth factor β (TGF-β) family [activins, Bone Morphogenetic Proteins (BMPs), and TGF-βs] signal by bringing together two type I and two type II receptors. Activin ...Ligands in the transforming growth factor β (TGF-β) family [activins, Bone Morphogenetic Proteins (BMPs), and TGF-βs] signal by bringing together two type I and two type II receptors. Activin receptor-like kinase-2 (ALK2) is the only type I receptor among the seven TGF-β type I receptors that interacts with both activin and BMP ligands. With BMPs, ALK2 acts as a signaling receptor to activate small mothers against decapentaplegic 1 (SMAD1)/5/8 signaling. Alternatively, with activins, such as Activin A (ActA), ALK2 forms nonsignaling complexes that negatively regulate ALK2 and ActA signaling. To gain insight into how ALK2 interacts with two distinct classes of ligands, we resolved the cryoelectron microscopy structure of ALK2 in complex with the type II receptor, ActRIIB, and the ligand, BMP6, in parallel with the corresponding structure with ALK3 for direct comparison. These structures demonstrate that ALK2 and ALK3 utilize different mechanisms to interact with BMP6 at the wrist interface, with ALK2 relying on BMP6 glycosylation and ALK3 relying on a salt bridge. Modeling of ALK2:ActA reveals that binding relies on ActA's fingertip region, mirroring the interaction of ActA with its other receptor, ALK4. Our results demonstrate that ALK2 is a "hybrid" receptor that incorporates features of BMP type I receptors such as ALK3 at the wrist interface and an activin type I receptor such as ALK4 at the fingertip.
History
DepositionDec 13, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 3, 2025Provider: repository / Type: Initial release
Revision 1.1Sep 10, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: receptor protein serine/threonine kinase
D: receptor protein serine/threonine kinase
E: Bone Morphogenetic Protein 6 (BMP6)
F: ActRIIB
B: Bone Morphogenetic Protein 6 (BMP6)
A: ActRIIB
hetero molecules


Theoretical massNumber of molelcules
Total (without water)88,85514
Polymers85,2186
Non-polymers3,6378
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1chain "A"
d_2ens_1chain "F"
d_1ens_2chain "E"
d_2ens_2chain "B"
d_1ens_3chain "D"
d_2ens_3chain "C"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ens_1THRTHRPROPROAF26 - 1178 - 99
d_12ens_1NAGNAGNAGNAGKK1
d_13ens_1NAGNAGNAGNAGLL1
d_14ens_1NAGNAGNAGNAGLL2
d_15ens_1NAGNAGNAGNAGKK2
d_16ens_1BMABMABMABMAKK3
d_21ens_1THRTHRPROPROFD26 - 1178 - 99
d_22ens_1NAGNAGNAGNAGHH1
d_23ens_1NAGNAGNAGNAGII1
d_24ens_1NAGNAGNAGNAGII2
d_25ens_1NAGNAGNAGNAGHH2
d_26ens_1BMABMABMABMAHH3
d_11ens_2THRTHRHISHISEC410 - 5131 - 104
d_12ens_2NAGNAGNAGNAGGG1
d_13ens_2NAGNAGNAGNAGGG2
d_14ens_2BMABMABMABMAGG3
d_21ens_2THRTHRHISHISBE410 - 5131 - 104
d_22ens_2NAGNAGNAGNAGJJ1
d_23ens_2NAGNAGNAGNAGJJ2
d_24ens_2BMABMABMABMAJJ3
d_11ens_3NAGNAGNAGNAGDN201
d_12ens_3THRTHRPROPRODB50 - 14126 - 117
d_21ens_3NAGNAGNAGNAGCM201
d_22ens_3THRTHRPROPROCA50 - 14126 - 117

NCS ensembles :
ID
ens_1
ens_2
ens_3

NCS oper:
IDCodeMatrixVector
1given(-0.999760798898, 0.0218665383211, -0.000446641460711), (-0.0218655587219, -0.999758732267, -0.00209155411588), (-0.000492268748764, -0.00208128774875, 0.999997712954)298.907804495, 306.128872005, 0.787260414024
2given(-0.999990642675, -0.000180576184703, 0.0043222626609), (0.00014639524269, -0.999968727494, -0.00790712353515), (0.00432355533112, -0.00790641678694, 0.999959396897)301.418834653, 303.154518105, 0.450635955366
3given(-0.999942531839, 0.00237806323544, -0.0104536039349), (-0.00231849640592, -0.999981029237, -0.0057066401154), (-0.0104669763731, -0.00568207552214, 0.999929075697)303.26146171, 303.218021878, 2.7339056546

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Components

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Protein , 3 types, 6 molecules CDEBFA

#1: Protein receptor protein serine/threonine kinase


Mass: 15898.968 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: Bmpr1a / Production host: Cricetulus griseus (Chinese hamster)
References: UniProt: A0A8C2MQM3, receptor protein serine/threonine kinase
#2: Protein Bone Morphogenetic Protein 6 (BMP6)


Mass: 11776.574 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#3: Protein ActRIIB


Mass: 14933.380 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Fusion protein, ActRIIB fused to antibody linker/hinge region
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)

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Sugars , 3 types, 8 molecules

#4: Polysaccharide
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 4 / Source method: obtained synthetically
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#5: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#6: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Details

Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Ternary complex of ALK3-ActRIIB with BMP6 / Type: COMPLEX / Details: ALK3-ActRIIB fused by Antibody Hinge region. / Entity ID: #3 / Source: RECOMBINANT
Molecular weightValue: 0.08 MDa / Experimental value: NO
Source (natural)Organism: Cricetulus griseus (Chinese hamster)
Source (recombinant)Organism: Cricetulus griseus (Chinese hamster)
Buffer solutionpH: 7.5 / Details: 50mM Tris-HCL, 100mM NaCl
Buffer component
IDConc.NameFormulaBuffer-ID
150 mMTrisC4H11NO31
2100 mMsodium chlorideNaCl1
SpecimenConc.: 3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Sample was monodisperse, following purification over size exclusion chromatography.
Specimen supportGrid material: GOLD
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 3400 nm / Nominal defocus min: 1000 nm / Alignment procedure: BASIC
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21.2_5419 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 133522 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Details: Initial fitting was performed in ChimeraX and real-space refinement was carried out within Phenix.
Atomic model building

3D fitting-ID: 1 / Source name: PDB / Type: experimental model

IDPDB-IDPdb chain-IDAccession codeChain-IDInitial refinement model-ID
12GOO

2goo

E2GOOE1
26MAC

6mac

C6MACC2
36OMO

6omo

I6OMOI3
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 60.52 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00354932
ELECTRON MICROSCOPYf_angle_d0.72256694
ELECTRON MICROSCOPYf_chiral_restr0.0515764
ELECTRON MICROSCOPYf_plane_restr0.0065858
ELECTRON MICROSCOPYf_dihedral_angle_d8.2831994
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2FAELECTRON MICROSCOPYNCS constraints2.43963782839E-13
ens_2d_2CEELECTRON MICROSCOPYNCS constraints1.45420956289E-12
ens_3d_2NDELECTRON MICROSCOPYNCS constraints2.93796189551E-12

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