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

Abstract

Misoprostol is a life-saving drug in many developing countries for women at risk of post-partum hemorrhaging due 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 ring structure. Modelling of selective agonists in 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.

Structural insights into melatonin receptors

“…Even within the α‐branch of class A, lysophosphatidic acid, sphingosine‐1‐phosphate, and cannabinoid receptors , which lack the canonical class A disulfide bridge between TM3 and ECL2, close off their binding sites mostly using their N terminus with minor ECL2 contributions. In contrast, prostaglandin receptors and rhodopsin display a tight lid formed from ECL2 with a β‐hairpin constrained to TM3 by the canonical class A disulfide bridge. The ECL2 backbone and disulfide location of MT receptors overlap remarkably well with that of solved prostaglandin and rhodopsin structures (Fig.…”

“…In case of GPCRs, crystals are typically delivered to the intersection with the XFEL beam by injection within their growth medium using viscous media LCP injectors . During the last five years, about a dozen novel GPCR structures have been determined benefiting from XFEL data collection . In the case of MT receptors, using the CXI beamline at the Linac Coherent Light Source (LCLS) we were able to obtain structures of MT 1 and MT 2 bound to different agonists at resolutions between 2.8 and 3.3 Å (Table )—we attribute the remarkable gain in resolution for MT 1 at XFEL sources to the specific packing of the receptor in alternating layers with strong and weak contacts (Fig.…”

Towards an Optimal Sample Delivery Method for Serial Crystallography at XFEL

“…Hydrophilic matrixes (hyaluronic acid, hydroxyethyl cellulose, sodium carboxymethyl cellulose and agarose) have the additional advantage of having a much lower background scattering comparing to LCP, which has a prominent background at the resolution range of 4-5 Å, thus improving the signal-to-noise ratio, which is especially useful during experimental phasing [114,115,120]. The LCP jet has proven its potential and it has become the standard jetting method for de novo structure determination at XFEL for GPCR microcrystals (<5 µm 3 ) [53,54,56,[123][124][125].…”

A guide to sample delivery systems for serial crystallography

“…In 1996, Landau [58] first crystallized the bacterial rhodopsin protein by the LCP technique. Subsequently, a variety of membrane protein structures, including G protein-coupled receptors (GPCRs), was obtained by LCP technology [59][60][61][62][63][64][65]. GPCRs mediate signaling pathways and participate in the regulation of a variety of physiological processes and are important drug targets.…”