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

Journal Article · · Nature Chemical Biology
 [1];  [1];  [2];  [1];  [1];  [3];  [4];  [5];  [6];  [1];  [1];  [7];  [7];  [7];  [3];  [8];  [8];  [9];  [1]
  1. Univ. of Southern California, Los Angeles, CA (United States)
  2. Domain Therapeutics NA Inc., Montreal (Canada)
  3. ShanghaiTech Univ., Shanghai (China)
  4. SLAC National Accelerator Lab., Menlo Park, CA (United States); Stanford Univ., Palo Alto, CA (United States)
  5. SLAC National Accelerator Lab., Menlo Park, CA (United States)
  6. Univ. of Southern California, Los Angeles, CA (United States); Moscow Institute of Physics & Technology, Dolgoprudn (Russia); Skolkovo Institute of Science and Technology, Moscow (Russia)
  7. Arizona State Univ., Tempe, AZ (United States)
  8. Univ. of Southern California, Los Angeles, CA (United States); Moscow Institute of Physics & Technology, Dolgoprudn (Russia)
  9. GPCR Consortium, San Marcos, CA (United States)
+ Show Author Affiliations
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.
Research Organization:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Sponsoring Organization:
USDOE
Grant/Contract Number:
AC02-76SF00515
OSTI ID:
1490668
Alternate ID(s):
OSTI ID: 1493799
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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Cited By (9)

Emerging structural biology of lipid G protein-coupled receptors: Structural Biology of Lipid G Protein-Coupled Receptors journal January 2019
Improved protein structure prediction using potentials from deep learning journal January 2020
Small-scale approach for precrystallization screening in GPCR X-ray crystallography journal November 2019
An outlook on using serial femtosecond crystallography in drug discovery journal May 2019
A fixed-target platform for serial femtosecond crystallography in a hydrated environment journal January 2020
A guide to sample delivery systems for serial crystallography journal August 2019
Structural insights into melatonin receptors journal November 2019
Improved homology modeling of the human & rat EP4 prostanoid receptors journal August 2019
A fixed-target platform for serial femtosecond crystallography in a hydrated environment text January 2020

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60 APPLIED LIFE SCIENCES