Misoprostol is a life-saving drug in many developing countries for women at risk of post-partum hemorrhaging owing to its affordability, stability, ease of administration and clinical efficacy. However, misoprostol lacks receptor and tissue selectivities, and thus its use is accompanied by a number of serious side effects. The development of pharmacological agents combining the advantages of misoprostol with improved selectivity is hindered by the absence of atomic details of misoprostol action in labor induction. Here, we present the 2.5 Å resolution crystal structure of misoprostol free-acid form bound to the myometrium labor-inducing prostaglandin E2 receptor 3 (EP3). The active state structure reveals a completely enclosed binding pocket containing a structured water molecule that coordinates misoprostol's ring structure. Modeling of selective agonists in the EP3 structure reveals rationales for selectivity. These findings will provide the basis for the next generation of uterotonic drugs that will be suitable for administration in low resource settings.
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The misoprostol-FA EP3 receptor complex structure coordinates and structure factors are available via the Protein Data Bank (PDB) accession code 6M9T.
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This research was supported by NIH R35 GM127086 (V.C.), R21 DA042298 (W.L.), R01 GM124152 (W.L.), the STC Program of the National Science Foundation through BioXFEL (No. 1231306) (U.W. and W.L.), the Russian Science Foundation (project no. 16-14-10273), and the GPCR Consortium. M.A. was supported by a Canadian Institute of Health and Research (CIHR) Postdoctoral Fellowship Award. C.G. acknowledges the Panofsky Fellowship from SLAC National Accelerator Laboratory and Stanford University for financial support. P.P. and V.K. acknowledge the Russian Foundation for Basic Research (RFBR No.18-34-00990). Parts of this research were carried out at the LCLS, a National User Facility operated by Stanford University on behalf of the US Department of Energy and is supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under contract no. DE-AC0276SF00515, and at the GM/CA CAT of the Argonne Photon Source, Argonne National Laboratory. We thank A. Walker for assistance in manuscript preparation; M. Chu, K. Villiers and C. Hanson for baculovirus expression and mammalian cell culture, and N. Sawyer for helpful suggestions. We are grateful to F. Badeaux and E. Audet-Badeaux for their encouragement and support.
B.B is an employee of Domain Therapeutics NA, a company focused on GPCR drug discovery that sells and licenses the cell signaling kit used in this study. All other authors declare no competing interests.
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Audet, M., White, K.L., Breton, B. et al. Crystal structure of misoprostol bound to the labor inducer prostaglandin E2 receptor. Nat Chem Biol 15, 11–17 (2019). https://doi.org/10.1038/s41589-018-0160-y
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