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- EMDB-48883: CryoEM structure of ALK2-ActRIIB bound to BMP6 -

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Basic information

Entry
Database: EMDB / ID: EMD-48883
TitleCryoEM structure of ALK2-ActRIIB bound to BMP6
Map data
Sample
  • Complex: Ternary complex of ALK2-ActRIIB with BMP6
    • Protein or peptide: Activin receptor type-2B
    • Protein or peptide: Bone morphogenetic protein 6
    • Protein or peptide: Activin receptor type-1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: beta-D-mannopyranose
KeywordsTGFB / Signaling / Receptor / Bone Morphogenetic Protein / ALK2 / Ligand / Growth Factor / SIGNALING PROTEIN
Function / homology
Function and homology information


positive regulation of aldosterone biosynthetic process / positive regulation of aldosterone secretion / Regulation of signaling by NODAL / activin receptor activity / activin receptor activity, type II / lymphatic endothelial cell differentiation / positive regulation of activin receptor signaling pathway / enzyme activator complex / venous blood vessel development / negative regulation of adherens junction organization ...positive regulation of aldosterone biosynthetic process / positive regulation of aldosterone secretion / Regulation of signaling by NODAL / activin receptor activity / activin receptor activity, type II / lymphatic endothelial cell differentiation / positive regulation of activin receptor signaling pathway / enzyme activator complex / venous blood vessel development / negative regulation of adherens junction organization / endocardial cushion cell fate commitment / positive regulation of chondrocyte differentiation / lymphangiogenesis / trophoblast cell migration / mitral valve morphogenesis / BMP receptor complex / cardiac muscle cell fate commitment / BMP receptor activity / atrial septum primum morphogenesis / endocardial cushion fusion / retina vasculature development in camera-type eye / positive regulation of endothelial cell differentiation / positive regulation of cardiac epithelial to mesenchymal transition / acute inflammatory response / positive regulation of determination of dorsal identity / type B pancreatic cell development / transforming growth factor beta receptor activity, type I / embryonic foregut morphogenesis / BMP receptor binding / smooth muscle cell differentiation / activin receptor complex / activin receptor activity, type I / endocardial cushion formation / artery development / eye development / pharyngeal system development / transmembrane receptor protein serine/threonine kinase activity / receptor protein serine/threonine kinase / endochondral ossification / activin binding / pattern specification process / cellular response to BMP stimulus / Signaling by BMP / male genitalia development / Signaling by Activin / negative regulation of cell-cell adhesion mediated by cadherin / positive regulation of vascular permeability / activin receptor signaling pathway / negative regulation of activin receptor signaling pathway / Signaling by NODAL / embryonic heart tube morphogenesis / gastrulation with mouth forming second / positive regulation of lipopolysaccharide-mediated signaling pathway / pancreas development / dorsal/ventral pattern formation / transforming growth factor beta binding / cartilage development / kinase activator activity / determination of left/right symmetry / negative regulation of ossification / atrioventricular valve morphogenesis / neural crest cell migration / anterior/posterior pattern specification / negative regulation of cold-induced thermogenesis / cell surface receptor protein serine/threonine kinase signaling pathway / insulin secretion / skeletal system morphogenesis / organ growth / growth factor binding / branching involved in blood vessel morphogenesis / ventricular septum morphogenesis / negative regulation of G1/S transition of mitotic cell cycle / SMAD binding / odontogenesis of dentin-containing tooth / mesoderm development / germ cell development / roof of mouth development / peptide hormone binding / positive regulation of intracellular signal transduction / mesoderm formation / response to magnesium ion / positive regulation of SMAD protein signal transduction / regulation of ossification / blood vessel remodeling / response to retinoic acid / positive regulation of bone mineralization / positive regulation of osteoblast differentiation / response to glucose / negative regulation of signal transduction / BMP signaling pathway / positive regulation of endothelial cell proliferation / positive regulation of neuron differentiation / protein serine/threonine/tyrosine kinase activity / transforming growth factor beta receptor signaling pathway / lung development / protein tyrosine kinase binding / response to glucocorticoid / cytokine activity / positive regulation of epithelial cell proliferation / response to activity
Similarity search - Function
GS domain / Transforming growth factor beta type I GS-motif / GS domain profile. / GS motif / TGF-beta, propeptide / TGF-beta propeptide / Activin types I and II receptor domain / Transforming growth factor beta, conserved site / Activin types I and II receptor domain / TGF-beta family signature. ...GS domain / Transforming growth factor beta type I GS-motif / GS domain profile. / GS motif / TGF-beta, propeptide / TGF-beta propeptide / Activin types I and II receptor domain / Transforming growth factor beta, conserved site / Activin types I and II receptor domain / TGF-beta family signature. / Transforming growth factor-beta-related / Transforming growth factor-beta (TGF-beta) family / Transforming growth factor-beta, C-terminal / Transforming growth factor beta like domain / TGF-beta family profile. / Ser/Thr protein kinase, TGFB receptor / Cystine-knot cytokine / 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
Bone morphogenetic protein 6 / Activin receptor type-1 / Activin receptor type-2B
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsGoebel EJ / Saotome K / Franklin MC
Funding support United States, 1 items
OrganizationGrant numberCountry
Other private United States
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
DepositionFeb 3, 2025-
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_48883.png

Downloads & links

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Map

FileDownload / File: emd_48883.map.gz / Format: CCP4 / Size: 137.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 330 pix.
= 276.87 Å		0.84 Å/pix.
x 330 pix.
= 276.87 Å		0.84 Å/pix.
x 330 pix.
= 276.87 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.839 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0121
Minimum - Maximum-0.2000316 - 0.4781934
Average (Standard dev.)-0.0008401436 (±0.010092963)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions330330330
Spacing330330330
CellA=B=C: 276.87 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_48883_msk_1.map
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Additional map: #2

Fileemd_48883_additional_1.map
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Additional map: #1

Fileemd_48883_additional_2.map
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Half map: #2

Fileemd_48883_half_map_1.map
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Sample components

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Entire : Ternary complex of ALK2-ActRIIB with BMP6

EntireName: Ternary complex of ALK2-ActRIIB with BMP6
Components
  • Complex: Ternary complex of ALK2-ActRIIB with BMP6
    • Protein or peptide: Activin receptor type-2B
    • Protein or peptide: Bone morphogenetic protein 6
    • Protein or peptide: Activin receptor type-1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: beta-D-mannopyranose

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Supramolecule #1: Ternary complex of ALK2-ActRIIB with BMP6

SupramoleculeName: Ternary complex of ALK2-ActRIIB with BMP6 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 / Details: ALK2-ActRIIB fused by Antibody Hinge region
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 80 KDa

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Macromolecule #1: Activin receptor type-2B

MacromoleculeName: Activin receptor type-2B / 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: 14.93338 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString:
SGRGEAETRE CIYYNANWEL ERTNQSGLER CEGEQDKRLH CYASWRNSSG TIELVKKGCW LDDFNCYDRQ ECVATEENPQ VYFCCCEGN FCNERFTHLP EAGGPEVTYE PPPTAPTGGG THTCPPCPAP ELLG

UniProtKB: Activin receptor type-2B

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Macromolecule #2: Bone morphogenetic protein 6

MacromoleculeName: Bone morphogenetic protein 6 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 15.695711 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString:
SASSRRRQQS RNRSTQSQDV ARVSSASDYN SSELKTACRK HELYVSFQDL GWQDWIIAPK GYAANYCDGE CSFPLNAHMN ATNHAIVQT LVHLMNPEYV PKPCCAPTKL NAISVLYFDD NSNVILKKYR NMVVRACGCH

UniProtKB: Bone morphogenetic protein 6

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Macromolecule #3: Activin receptor type-1

MacromoleculeName: Activin receptor type-1 / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein serine/threonine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.18988 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString:
MEDEKPKVNP KLYMCVCEGL SCGNEDHCEG QQCFSSLSIN DGFHVYQKGC FQVYEQGKMT CKTPPSPGQA VECCQGDWCN RNITAQLPT KGKSFPGTQN FHLETGGGTH TCPPCPAPEL LG

UniProtKB: Activin receptor type-1

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

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

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Macromolecule #6: beta-D-mannopyranose

MacromoleculeName: beta-D-mannopyranose / type: ligand / ID: 6 / Number of copies: 2 / Formula: BMA
Molecular weightTheoretical: 180.156 Da
Chemical component information

ChemComp-BMA:
beta-D-mannopyranose

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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 mono disperse 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: 2.4 µm / Nominal defocus min: 0.8 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: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 42185
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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Atomic model buiding 1

Initial model
PDB IDChain

7yru

chain_id: A, 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-9n4k:
CryoEM structure of ALK2-ActRIIB bound to BMP6

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