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Nat Chem Biol. 2019 Jan;15(1):11-17. doi: 10.1038/s41589-018-0160-y. Epub 2018 Dec 3.

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

Author information

1
Departments of Biological Sciences and Chemistry, Bridge Institute, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, USA.
2
Domain Therapeutics NA Inc., Montreal, Canada.
3
iHuman Institute, ShanghaiTech University, Shanghai, China.
4
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
5
Biosciences Division, SLAC National Accelerator Laboratory, Menlo Park, CA, USA.
6
Department of Structural Biology, School of Medicine, Stanford University, Palo Alto, CA, USA.
7
Linac Coherent Light Source, SLAC National Accelerator Laboratory, Menlo Park, CA, USA.
8
Moscow Institute of Physics & Technology, Dolgoprudn, Russia.
9
Skolkovo Institute of Science and Technology, Moscow, Russia.
10
Biodesign Center for Applied Structural Discovery, Biodesign Institute, School of Molecular Sciences, Arizona State University, Tempe, AZ, USA.
11
GPCR Consortium, San Marcos, CA, USA.
12
Departments of Biological Sciences and Chemistry, Bridge Institute, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, USA. stevens@usc.edu.

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.

PMID:
30510194
PMCID:
PMC6289721
DOI:
10.1038/s41589-018-0160-y
[Indexed for MEDLINE]
Free PMC Article

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