Faculty Collaboration Database

Crystal structure of misoprostol bound to the labor inducer prostaglandin E₂ receptor. Nat Chem Biol 2019 Jan;15(1):11-17

Date

12/05/2018

Pubmed ID

30510194

Pubmed Central ID

PMC6289721

DOI

10.1038/s41589-018-0160-y

Scopus ID

2-s2.0-85058043420 (requires institutional sign-in at Scopus site)   40 Citations

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.

Author List

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

Author

Wei Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Binding Sites
Crystallography, X-Ray
Dinoprostone
Humans
Misoprostol
Molecular Docking Simulation
Mutagenesis, Site-Directed
Protein Conformation
Receptors, Prostaglandin E, EP3 Subtype
Signal Transduction
Water