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.

doi:10.1038/s41589-018-0160-y

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

Journal Article · 02 December 2018 · Nature Chemical Biology

DOI: https://doi.org/10.1038/s41589-018-0160-y · OSTI ID:1490668

Audet, Martin ^[1]; White, Kate L. ^[1]; Breton, Billy ^[2]; Zarzycka, Barbara ^[1]; Han, Gye Won ^[1]; Lu, Yan ^[3]; Gati, Cornelius ^[4];

^[5]; Popov, Petr ^[6]; Velasquez, Jeffrey ^[1]; Manahan, David ^[1]; Hu, Hao ^[7]; Weierstall, Uwe ^[7]; Liu, Wei ^[7]; Shui, Wenqing ^[3];

^[8];

^[8]; Hanson, Michael A. ^[9];

^[1]

Univ. of Southern California, Los Angeles, CA (United States)
Domain Therapeutics NA Inc., Montreal (Canada)
ShanghaiTech Univ., Shanghai (China)
SLAC National Accelerator Lab., Menlo Park, CA (United States); Stanford Univ., Palo Alto, CA (United States)
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Univ. of Southern California, Los Angeles, CA (United States); Moscow Institute of Physics & Technology, Dolgoprudn (Russia); Skolkovo Institute of Science and Technology, Moscow (Russia)
Arizona State Univ., Tempe, AZ (United States)
Univ. of Southern California, Los Angeles, CA (United States); Moscow Institute of Physics & Technology, Dolgoprudn (Russia)
GPCR Consortium, San Marcos, CA (United States)

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. Lastly, 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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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1490668

Journal Information:: Nature Chemical Biology, Journal Name: Nature Chemical Biology Journal Issue: 1 Vol. 15; ISSN 1552-4450

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Implementing at-scale, community-based distribution of misoprostol tablets to mothers in the third stage of labor for the prevention of postpartum haemorrhage in Sokoto State, Nigeria: Early Results and Lessons Learned: Datasets Orobaton, Nosakhare; Abdulazeez, Jumare; Abegunde, Dele figshare https://doi.org/10.6084/m9.figshare.4616350	dataset	January 2017
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An outlook on using serial femtosecond crystallography in drug discovery Mishin, Alexey; Gusach, Anastasiia; Luginina, Aleksandra Expert Opinion on Drug Discovery, Vol. 14, Issue 9 https://doi.org/10.1080/17460441.2019.1626822	journal	May 2019
A fixed-target platform for serial femtosecond crystallography in a hydrated environment Shelby, M. L.; Gilbile, D.; Grant, T. D. IUCrJ, Vol. 7, Issue 1 https://doi.org/10.1107/s2052252519014003	journal	January 2020
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