6M9T

Crystal structure of EP3 receptor bound to misoprostol-FA

Summary for 6M9T

• Entry DOI: 10.2210/pdb6m9t/pdb
• Descriptor: Prostaglandin E2 receptor EP3 subtype, Endolysin chimera, (11alpha,12alpha,13E,16S)-11,16-dihydroxy-16-methyl-9-oxoprost-13-en-1-oic acid, SULFATE ION, ... (6 entities in total)
• Functional Keywords: gpcr, prostaglandin e2 receptor 3 (ep3), prostaglandin analogue, membrane protein, misoprostol-fa (biologically active free acid), xfel, lcp, t4l
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 62262.59

Authors

Audet, M.,White, K.L.,Breton, B.,Zarzycka, B.,Han, G.W.,Lu, Y.,Gati, C.,Batyuk, A.,Popov, P.,Velasquez, J.,Manahan, D.,Hu, H.,Weierstall, U.,Liu, W.,Shui, W.,Katrich, V.,Cherezov, V.,Hanson, M.A.,Stevens, R.C. (deposition date: 2018-08-24, release date: 2018-12-05, Last modification date: 2024-11-06)

Primary citation

Audet, M.,White, K.L.,Breton, B.,Zarzycka, B.,Han, G.W.,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, M.A.,Stevens, R.C.
Crystal structure of misoprostol bound to the labor inducer prostaglandin E2receptor.
Nat. Chem. Biol., 15:11-17, 2019

PubMed 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 E 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.

PubMed: 30510194
DOI: 10.1038/s41589-018-0160-y

Experimental method

X-RAY DIFFRACTION (2.5 Å)