3Q4T
Crystal structure of Activin receptor type-IIA (ACVR2A) kinase domain in complex with dorsomorphin
Summary for 3Q4T
| Entry DOI | 10.2210/pdb3q4t/pdb |
| Descriptor | Activin receptor type-2A, 6-[4-(2-piperidin-1-ylethoxy)phenyl]-3-pyridin-4-ylpyrazolo[1,5-a]pyrimidine, SULFATE ION, ... (6 entities in total) |
| Functional Keywords | structural genomics consortium, sgc, protein kinase, transferase |
| Biological source | Homo sapiens (human) |
| Cellular location | Membrane; Single-pass type I membrane protein: P27037 |
| Total number of polymer chains | 2 |
| Total formula weight | 75778.41 |
| Authors | Chaikuad, A.,Alfano, I.,Mahajan, P.,Cooper, C.D.O.,Sanvitale, C.,Vollmar, M.,Krojer, T.,Muniz, J.R.C.,Raynor, J.,von Delft, F.,Weigelt, J.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Bullock, A.,Structural Genomics Consortium (SGC) (deposition date: 2010-12-24, release date: 2011-02-09, Last modification date: 2023-09-13) |
| Primary citation | Horbelt, D.,Boergermann, J.H.,Chaikuad, A.,Alfano, I.,Williams, E.,Lukonin, I.,Timmel, T.,Bullock, A.N.,Knaus, P. Small Molecules Dorsomorphin and LDN-193189 Inhibit Myostatin/GDF8 Signaling and Promote Functional Myoblast Differentiation. J.Biol.Chem., 290:3390-3404, 2015 Cited by 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. PubMed: 25368322DOI: 10.1074/jbc.M114.604397 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.96 Å) |
Structure validation
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