Crystal structure of misoprostol bound to the labor inducer prostaglandin E2 receptor

Martin Audet, Kate L. White, Billy Breton, Barbara Zarzycka, Gye Won Han, Yan Lu, Cornelius Gati, Alexander Batyuk, Petr Popov, Jeffrey Velasquez, David Manahan, Hao Hu, Uwe Weierstall, Wei Liu, Wenqing Shui, Vsevolod Katritch, Vadim Cherezov, Michael A. Hanson, Raymond C. Stevens

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)11-17
Number of pages7
JournalNature Chemical Biology
Volume15
Issue number1
DOIs
StatePublished - Jan 1 2019

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Prostaglandin Receptors
Misoprostol
Dinoprostone
Induced Labor
Myometrium
Pharmaceutical Preparations
Developing Countries
Pharmacology
Water

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Audet, M., White, K. L., Breton, B., Zarzycka, B., Han, G. W., Lu, Y., ... Stevens, R. C. (2019). Crystal structure of misoprostol bound to the labor inducer prostaglandin E2 receptor. Nature Chemical Biology, 15(1), 11-17. https://doi.org/10.1038/s41589-018-0160-y

Crystal structure of misoprostol bound to the labor inducer prostaglandin E2 receptor. / Audet, Martin; White, Kate L.; Breton, Billy; Zarzycka, Barbara; Han, Gye Won; Lu, Yan; Gati, Cornelius; Batyuk, Alexander; Popov, Petr; Velasquez, Jeffrey; Manahan, David; Hu, Hao; Weierstall, Uwe; Liu, Wei; Shui, Wenqing; Katritch, Vsevolod; Cherezov, Vadim; Hanson, Michael A.; Stevens, Raymond C.

In: Nature Chemical Biology, Vol. 15, No. 1, 01.01.2019, p. 11-17.

Research output: Contribution to journalArticle

Audet, M, White, KL, Breton, B, Zarzycka, B, Han, GW, Lu, Y, Gati, C, Batyuk, A, Popov, P, Velasquez, J, Manahan, D, Hu, H, Weierstall, U, Liu, W, Shui, W, Katritch, V, Cherezov, V, Hanson, MA & Stevens, RC 2019, 'Crystal structure of misoprostol bound to the labor inducer prostaglandin E2 receptor' Nature Chemical Biology, vol. 15, no. 1, pp. 11-17. https://doi.org/10.1038/s41589-018-0160-y
Audet, Martin ; White, Kate L. ; Breton, Billy ; Zarzycka, Barbara ; Han, Gye Won ; Lu, Yan ; Gati, Cornelius ; Batyuk, Alexander ; Popov, Petr ; Velasquez, Jeffrey ; Manahan, David ; Hu, Hao ; Weierstall, Uwe ; Liu, Wei ; Shui, Wenqing ; Katritch, Vsevolod ; Cherezov, Vadim ; Hanson, Michael A. ; Stevens, Raymond C. / Crystal structure of misoprostol bound to the labor inducer prostaglandin E2 receptor. In: Nature Chemical Biology. 2019 ; Vol. 15, No. 1. pp. 11-17.
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