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- PDB-9n4k: CryoEM structure of ALK2-ActRIIB bound to BMP6 -

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Basic information

Entry
Database: PDB / ID: 9n4k
TitleCryoEM structure of ALK2-ActRIIB bound to BMP6
Components
  • (Activin receptor type- ...) x 2
  • Bone morphogenetic protein 6
KeywordsSIGNALING PROTEIN / TGFB / Signaling / Receptor / Bone Morphogenetic Protein / ALK2 / Ligand / Growth Factor
Function / homology
Function and homology information


positive regulation of aldosterone biosynthetic process / positive regulation of aldosterone secretion / Regulation of signaling by NODAL / enzyme activator complex / activin receptor activity / activin receptor activity, type II / lymphatic endothelial cell differentiation / positive regulation of activin receptor signaling pathway / negative regulation of adherens junction organization / endocardial cushion cell fate commitment ...positive regulation of aldosterone biosynthetic process / positive regulation of aldosterone secretion / Regulation of signaling by NODAL / enzyme activator complex / activin receptor activity / activin receptor activity, type II / lymphatic endothelial cell differentiation / positive regulation of activin receptor signaling pathway / negative regulation of adherens junction organization / endocardial cushion cell fate commitment / venous blood vessel development / lymphangiogenesis / mitral valve morphogenesis / trophoblast cell migration / BMP receptor complex / positive regulation of chondrocyte differentiation / BMP receptor activity / endocardial cushion fusion / cardiac muscle cell fate commitment / atrial septum primum morphogenesis / retina vasculature development in camera-type eye / positive regulation of cardiac epithelial to mesenchymal transition / positive regulation of endothelial cell differentiation / acute inflammatory response / type B pancreatic cell development / positive regulation of determination of dorsal identity / transforming growth factor beta receptor activity, type I / embryonic foregut morphogenesis / smooth muscle cell differentiation / activin receptor activity, type I / activin receptor complex / artery development / BMP receptor binding / endochondral ossification / endocardial cushion formation / pharyngeal system development / receptor protein serine/threonine kinase / eye development / transmembrane receptor protein serine/threonine kinase activity / activin binding / cellular response to BMP stimulus / Signaling by BMP / male genitalia development / pattern specification process / negative regulation of cell-cell adhesion mediated by cadherin / Signaling by Activin / negative regulation of activin receptor signaling pathway / positive regulation of vascular permeability / activin receptor signaling pathway / embryonic heart tube morphogenesis / Signaling by NODAL / gastrulation with mouth forming second / dorsal/ventral pattern formation / positive regulation of lipopolysaccharide-mediated signaling pathway / pancreas development / transforming growth factor beta binding / cartilage development / determination of left/right symmetry / negative regulation of ossification / kinase activator activity / atrioventricular valve morphogenesis / anterior/posterior pattern specification / negative regulation of cold-induced thermogenesis / cell surface receptor protein serine/threonine kinase signaling pathway / skeletal system morphogenesis / insulin secretion / organ growth / neural crest cell migration / growth factor binding / branching involved in blood vessel morphogenesis / negative regulation of G1/S transition of mitotic cell cycle / ventricular septum morphogenesis / SMAD binding / odontogenesis of dentin-containing tooth / mesoderm development / germ cell development / roof of mouth development / peptide hormone binding / mesoderm formation / positive regulation of intracellular signal transduction / positive regulation of SMAD protein signal transduction / response to magnesium ion / regulation of ossification / response to retinoic acid / positive regulation of osteoblast differentiation / positive regulation of bone mineralization / BMP signaling pathway / blood vessel remodeling / negative regulation of signal transduction / response to glucose / 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 / response to glucocorticoid / protein tyrosine kinase binding / 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
beta-D-mannopyranose / Bone morphogenetic protein 6 / Activin receptor type-1 / Activin receptor type-2B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsGoebel, E.J. / Saotome, K. / Franklin, M.C.
Funding support United States, 1items
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, 2025Deposition 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
A: Activin receptor type-2B
B: Bone morphogenetic protein 6
E: Bone morphogenetic protein 6
F: Activin receptor type-2B
C: Activin receptor type-1
D: Activin receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)90,49916
Polymers87,6386
Non-polymers2,86110
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Activin receptor type- ... , 2 types, 4 molecules AFCD

#1: Protein Activin receptor type-2B / Activin receptor type IIB / ACTR-IIB


Mass: 14933.380 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACVR2B / Production host: Cricetulus griseus (Chinese hamster)
References: UniProt: Q13705, receptor protein serine/threonine kinase
#3: Protein Activin receptor type-1 / Activin receptor type I / ACTR-I / Activin receptor-like kinase 2 / ALK-2 / Serine/threonine- ...Activin receptor type I / ACTR-I / Activin receptor-like kinase 2 / ALK-2 / Serine/threonine-protein kinase receptor R1 / SKR1 / TGF-B superfamily receptor type I / TSR-I


Mass: 13189.880 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACVR1, ACVRLK2 / Production host: Cricetulus griseus (Chinese hamster)
References: UniProt: Q04771, receptor protein serine/threonine kinase

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Protein , 1 types, 2 molecules BE

#2: Protein Bone morphogenetic protein 6 / BMP-6 / VG-1-related protein / VG-1-R / VGR-1


Mass: 15695.711 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BMP6, VGR / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P22004

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Sugars , 3 types, 10 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.: 2 / 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: 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.: 6 / 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
#6: Sugar ChemComp-BMA / beta-D-mannopyranose / beta-D-mannose / D-mannose / mannose


Type: D-saccharide, beta linking / Mass: 180.156 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H12O6
IdentifierTypeProgram
DManpbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
b-D-mannopyranoseCOMMON NAMEGMML 1.0
b-D-ManpIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
ManSNFG 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 ALK2-ActRIIB with BMP6 / Type: COMPLEX / Details: ALK2-ActRIIB fused by Antibody Hinge region / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.08 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
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 mono disperse 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: 2400 nm / Nominal defocus min: 800 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: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 42185 / 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
17YRU

7yru

A7YRUA1
26MAC

6mac

C6MACC2
36OMO

6omo

I6OMOI3

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