3Q4T

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

3Q4T の概要

• エントリーDOI: 10.2210/pdb3q4t/pdb
• 分子名称: 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)
• 機能のキーワード: structural genomics consortium, sgc, protein kinase, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P27037
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 75778.41

構造登録者

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) (登録日: 2010-12-24, 公開日: 2011-02-09, 最終更新日: 2023-09-13)

主引用文献

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

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: 25368322
DOI: 10.1074/jbc.M114.604397

実験手法

X-RAY DIFFRACTION (1.96 Å)