Structures of activin ligand traps using natural sets of type I and type II TGFβ receptors

Erich J Goebel; Chandramohan Kattamuri; Gregory R Gipson; Lavanya Krishnan; Moises Chavez; Magdalena Czepnik; Michelle C Maguire; Rosa Grenha; Maria Håkansson; Derek T Logan; Asya V Grinberg; Dianne Sako; Roselyne Castonguay; Ravindra Kumar; Thomas B Thompson

doi:10.1016/j.isci.2021.103590

Structures of activin ligand traps using natural sets of type I and type II TGFβ receptors

iScience. 2021 Dec 9;25(1):103590. doi: 10.1016/j.isci.2021.103590. eCollection 2022 Jan 21.

Authors

Affiliations

¹ Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, 231 Albert Sabin Way ML 0524, Cincinnati, OH 45267, USA.
² Acceleron Pharma, Inc., Cambridge, MA 02139, USA.
³ SARomics Biostructures AB, Medicon Village, Scheeletorget 1, 223 63, Lund, Sweden.
⁴ Dragonfly Therapeutics, Waltham, MA 02451, USA.

Abstract

The 30+ unique ligands of the TGFβ family signal by forming complexes using different combinations of type I and type II receptors. Therapeutically, the extracellular domain of a single receptor fused to an Fc molecule can effectively neutralize subsets of ligands. Increased ligand specificity can be accomplished by using the extracellular domains of both the type I and type II receptor to mimic the naturally occurring signaling complex. Here, we report the structure of one "type II-type I-Fc" fusion, ActRIIB-Alk4-Fc, in complex with two TGFβ family ligands, ActA, and GDF11, providing a snapshot of this therapeutic platform. The study reveals that extensive contacts are formed by both receptors, replicating the ternary signaling complex, despite the inherent low affinity of Alk4. Our study shows that low-affinity type I interactions support altered ligand specificity and can be visualized at the molecular level using this platform.

Keywords: Biochemistry; Molecular biology; Structural biology.

Abstract

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