3Q4T

Crystal structure of Activin receptor type-IIA (ACVR2A) kinase domain in complex with dorsomorphin


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.96 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.171 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Small Molecules Dorsomorphin and LDN-193189 Inhibit Myostatin/GDF8 Signaling and Promote Functional Myoblast Differentiation.

Horbelt, D.Boergermann, J.H.Chaikuad, A.Alfano, I.Williams, E.Lukonin, I.Timmel, T.Bullock, A.N.Knaus, P.

(2015) J Biol Chem 290: 3390-3404

  • DOI: https://doi.org/10.1074/jbc.M114.604397
  • Primary Citation of Related Structures:  
    3Q4T

  • PubMed Abstract: 

    GDF8, or myostatin, is a member of the TGF-β superfamily of secreted polypeptide growth factors. GDF8 is a potent negative regulator of myogenesis both in vivo and in vitro. We found that GDF8 signaling was inhibited by the small molecule ATP competitive inhibitors dorsomorphin and LDN-193189. These compounds were previously shown to be potent inhibitors of BMP signaling by binding to the BMP type I receptors ALK1/2/3/6. We present the crystal structure of the type II receptor ActRIIA with dorsomorphin and demonstrate that dorsomorphin or LDN-193189 target GDF8 induced Smad2/3 signaling and repression of myogenic transcription factors. As a result, both inhibitors rescued myogenesis in myoblasts treated with GDF8. As revealed by quantitative live cell microscopy, treatment with dorsomorphin or LDN-193189 promoted the contractile activity of myotubular networks in vitro. We therefore suggest these inhibitors as suitable tools to promote functional myogenesis.


  • Organizational Affiliation

    From the Institute for Chemistry-Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Activin receptor type-2A
A, B
322Homo sapiensMutation(s): 0 
Gene Names: ACVR2ACVR2A
EC: 2.7.11.30
UniProt & NIH Common Fund Data Resources
Find proteins for P27037 (Homo sapiens)
Explore P27037 
Go to UniProtKB:  P27037
PHAROS:  P27037
GTEx:  ENSG00000121989 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP27037
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
TAK
Query on TAK

Download Ideal Coordinates CCD File 
C [auth A],
Q [auth B]
6-[4-(2-piperidin-1-ylethoxy)phenyl]-3-pyridin-4-ylpyrazolo[1,5-a]pyrimidine
C24 H25 N5 O
XHBVYDAKJHETMP-UHFFFAOYSA-N
PG4
Query on PG4

Download Ideal Coordinates CCD File 
P [auth A]TETRAETHYLENE GLYCOL
C8 H18 O5
UWHCKJMYHZGTIT-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
R [auth B],
S [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
EDO
Query on EDO

Download Ideal Coordinates CCD File 
AA [auth B]
BA [auth B]
CA [auth B]
DA [auth B]
F [auth A]
AA [auth B],
BA [auth B],
CA [auth B],
DA [auth B],
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A],
L [auth A],
M [auth A],
N [auth A],
O [auth A],
T [auth B],
U [auth B],
V [auth B],
W [auth B],
X [auth B],
Y [auth B],
Z [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.96 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.171 
  • Space Group: P 65 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 110.1α = 90
b = 110.1β = 90
c = 206.911γ = 120
Software Package:
Software NamePurpose
GDAdata collection
PHASERphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2011-02-09
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2014-12-10
    Changes: Database references
  • Version 1.3: 2015-02-25
    Changes: Database references
  • Version 1.4: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description