Walker, Ryan G.Czepnik, MagdalenaGoebel, Erich J.McCoy, Jason C.Vujic, AnaCho, MiookOh, JuhyunAykul, SenemWalton, Kelly L.Schang, GauthierBernard, Daniel J.Hinck, Andrew P.Harrison, Craig A.Martinez-Hackert, ErikWagers, AmyLee, RichardThompson, Thomas B.2017-04-062017Walker, R. G., M. Czepnik, E. J. Goebel, J. C. McCoy, A. Vujic, M. Cho, J. Oh, et al. 2017. “Structural basis for potency differences between GDF8 and GDF11.” BMC Biology 15 (1): 19. doi:10.1186/s12915-017-0350-1. http://dx.doi.org/10.1186/s12915-017-0350-1.http://nrs.harvard.edu/urn-3:HUL.InstRepos:32072125Background: Growth/differentiation factor 8 (GDF8) and GDF11 are two highly similar members of the transforming growth factor β (TGFβ) family. While GDF8 has been recognized as a negative regulator of muscle growth and differentiation, there are conflicting studies on the function of GDF11 and whether GDF11 has beneficial effects on age-related dysfunction. To address whether GDF8 and GDF11 are functionally identical, we compared their signaling and structural properties. Results: Here we show that, despite their high similarity, GDF11 is a more potent activator of SMAD2/3 and signals more effectively through the type I activin-like receptor kinase receptors ALK4/5/7 than GDF8. Resolution of the GDF11:FS288 complex, apo-GDF8, and apo-GDF11 crystal structures reveals unique properties of both ligands, specifically in the type I receptor binding site. Lastly, substitution of GDF11 residues into GDF8 confers enhanced activity to GDF8. Conclusions: These studies identify distinctive structural features of GDF11 that enhance its potency, relative to GDF8; however, the biological consequences of these differences remain to be determined. Electronic supplementary material The online version of this article (doi:10.1186/s12915-017-0350-1) contains supplementary material, which is available to authorized users.en-USLigandsMyostatinReceptorStructureTransforming growth factor β (TGFβ)Journal Article2017-04-0610.1186/s12915-017-0350-1