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- EMDB-48301: CryoEM structure of ALK3-ActRIIB bound to BMP6 -

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Basic information

Entry
Database: EMDB / ID: EMD-48301
TitleCryoEM structure of ALK3-ActRIIB bound to BMP6
Map data
Sample
  • Complex: Ternary complex of ALK3-ActRIIB with BMP6
    • Protein or peptide: ActRIIB
  • Protein or peptide: receptor protein serine/threonine kinase
  • Protein or peptide: Bone Morphogenetic Protein 6 (BMP6)
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsSignaling / Ligand / Complex / Receptor / Type I / Type II / TGFB / BMP / SIGNALING PROTEIN
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 speciesCricetulus griseus (Chinese hamster) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsGoebel EJ / Saotome K / Franklin MC
Funding support1 items
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, 2024-
Header (metadata) releaseSep 3, 2025-
Map releaseSep 3, 2025-
UpdateSep 10, 2025-
Current statusSep 10, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48301.png

Downloads & links

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Map

FileDownload / File: emd_48301.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 360 pix.
= 302.04 Å		0.84 Å/pix.
x 360 pix.
= 302.04 Å		0.84 Å/pix.
x 360 pix.
= 302.04 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.839 Å
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Contour LevelBy AUTHOR: 0.00954
Minimum - Maximum-0.19762991 - 0.6197986
Average (Standard dev.)-0.00013791397 (±0.009366359)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 302.04 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_48301_msk_1.map
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Additional map: #2

Fileemd_48301_additional_1.map
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Additional map: #1

Fileemd_48301_additional_2.map
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Half map: #2

Fileemd_48301_half_map_1.map
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Sample components

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Entire : Ternary complex of ALK3-ActRIIB with BMP6

EntireName: Ternary complex of ALK3-ActRIIB with BMP6
Components
  • Complex: Ternary complex of ALK3-ActRIIB with BMP6
    • Protein or peptide: ActRIIB
  • Protein or peptide: receptor protein serine/threonine kinase
  • Protein or peptide: Bone Morphogenetic Protein 6 (BMP6)
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Ternary complex of ALK3-ActRIIB with BMP6

SupramoleculeName: Ternary complex of ALK3-ActRIIB with BMP6 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #3 / Details: ALK3-ActRIIB fused by Antibody Hinge region.
Source (natural)Organism: Cricetulus griseus (Chinese hamster)
Molecular weightTheoretical: 80 KDa

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Macromolecule #1: receptor protein serine/threonine kinase

MacromoleculeName: receptor protein serine/threonine kinase / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein serine/threonine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 15.898968 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString:
QNLDSMLHGT GMKSDLDQKK PENGVTLAPE DTLPFLKCYC SGHCPDDAIN NTCITNGHCF AIIEEDDQGE TTLASGCMKY EGSDFQCKD SPKAQLRRTI ECCRTNLCNQ YLQPTLPPVV IGPFFDGSIR DKTHTCPPCP APELLG

UniProtKB: receptor protein serine/threonine kinase

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Macromolecule #2: Bone Morphogenetic Protein 6 (BMP6)

MacromoleculeName: Bone Morphogenetic Protein 6 (BMP6) / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.776574 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString:
TACRKHELYV SFQDLGWQDW IIAPKGYAAN YCDGECSFPL NAHMNATNHA IVQTLVHLMN PEYVPKPCCA PTKLNAISVL YFDDNSNVI LKKYRNMVVR ACGCH

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Macromolecule #3: ActRIIB

MacromoleculeName: ActRIIB / type: protein_or_peptide / ID: 3
Details: Fusion protein, ActRIIB fused to antibody linker/hinge region
Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.93338 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString:
SGRGEAETRE CIYYNANWEL ERTNQSGLER CEGEQDKRLH CYASWRNSSG TIELVKKGCW LDDFNCYDRQ ECVATEENPQ VYFCCCEGN FCNERFTHLP EAGGPEVTYE PPPTAPTGGG THTCPPCPAP ELLG

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration3 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
50.0 mMC4H11NO3Tris
100.0 mMNaClsodium chloride

Details: 50mM Tris-HCL, 100mM NaCl
GridMaterial: GOLD
VitrificationCryogen name: ETHANE
DetailsSample was monodisperse, following purification over size exclusion chromatography.

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.4 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 133522
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationNumber classes: 121 / Avg.num./class: 1103

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Atomic model buiding 1

Initial model
PDB IDChain

2goo

chain_id: E, source_name: PDB, initial_model_type: experimental model

6mac

chain_id: C, source_name: PDB, initial_model_type: experimental model

6omo

chain_id: I, source_name: PDB, initial_model_type: experimental model
DetailsInitial fitting was performed in ChimeraX and real-space refinement was carried out within Phenix.
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

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

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