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Acknowledgements The work was supported by the Monash University Ramaciotti Centre for
Cryo-Electron Microscopy, the Monash MASSIVE high-performance computing facility, the
National Health and Medical Research Council of Australia (NHMRC) project grants (1061044,
1065410, 1120919 and 1126857) and NHMRC program grants (1055134 and 1150083), the Japan
Society for the Promotion of Science (JSPS) KAKENHI no. 18H06043 and Japan Science and
Technology Agency (JST) PRESTO no. 18069571 (to R.D.). P.M.S. and A.C. are NHMRC Senior
Principal Research Fellows and D.W. is an NHMRC Senior Research Fellow. S.G.B.F. is an ARC
Future Fellow. A.I. was funded by the PRIME JP17gm5910013 and the LEAP JP17gm0010004
from the Japan Agency for Medical Research and Development, and JSPS KAKENHI 17K08264.
We are grateful to G. Christopoulos, V. Julita, T. Fields, C. Lafuente, J. M. Minguez, G. C. Sanz
and F. Qu for assay and technical support.Author contributions P.Z. designed and performed most of the pharmacological studies
with assistance from T.T.T.; Y.-L.L. expressed and purified the complex; R.D. performed
cryo-sample preparation and imaging to acquire electron microscopy data; M.J.B. and
R.D. processed the electron microscopy data and performed electron microscopy map
calculations; M.J.B. built the model and performed refinement; M.M.F. performed the
mutagenesis studies, L.C. performed studies in the HEK293 CRISPR-knockout cells;
G.D. and C.A.R. designed, performed and analysed the molecular dynamics simulations;
F.S.W. and M.G.B. provided TT-OAD2. M.E.C., M.G.B. and K.W.S. designed and oversaw the
in vivo studies; P.Z., Y.-L.L., M.J.B., G.D., C.A.R., F.S.W., K.W.S., R.D., P.M.S. and D.W. performed
data analysis; P.Z., Y.-L.L., M.J.B., G.D., C.A.R., F.S.W., K.W.S., A.C., L.J.M., M.-W.W. and
R.D. assisted with data interpretation, figure and manuscript preparation; P.M.S. and
D.W. designed and supervised the project, interpreted the data and wrote the manuscript.Competing interests F.W.S., M.E.C. and K.W.S. are employees of Eli Lilly and Company.Additional information
Supplementary information is available for this paper at https://doi.org/10.1038/s41586-
019-1902-z.
Correspondence and requests for materials should be addressed to R.D., P.M.S. or D.W.
Peer review information Nature thanks Doryen Bubeck, Dave D’Alessio, Nita R. Shah and the
other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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