6m9t
From Proteopedia
Crystal structure of EP3 receptor bound to misoprostol-FA
Structural highlights
Function[PE2R3_HUMAN] Receptor for prostaglandin E2 (PGE2) (PubMed:8307176, PubMed:7883006, PubMed:8117308, PubMed:8135729, PubMed:7981210). The activity of this receptor can couple to both the inhibition of adenylate cyclase mediated by G(i) proteins, and to an elevation of intracellular calcium (PubMed:7883006, PubMed:8117308, PubMed:8135729, PubMed:7981210). Required for normal development of fever in response to pyrinogens, including IL1B, prostaglandin E2 and bacterial lipopolysaccharide (LPS). Required for normal potentiation of platelet aggregation by prostaglandin E2, and thus plays a role in the regulation of blood coagulation. Required for increased HCO3(-) secretion in the duodenum in response to mucosal acidification, and thereby contributes to the protection of the mucosa against acid-induced ulceration. Not required for normal kidney function, normal urine volume and osmolality (By similarity).[UniProtKB:P30557][1] [2] [3] [4] [5] Publication Abstract from PubMedMisoprostol 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 A 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. Crystal structure of misoprostol bound to the labor inducer prostaglandin E2 receptor.,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 Nat Chem Biol. 2019 Jan;15(1):11-17. doi: 10.1038/s41589-018-0160-y. Epub 2018, Dec 3. PMID:30510194[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Lysozyme | Audet, M | Batyuk, A | Breton, B | Cherezov, V | Gati, C | Han, G W | Hanson, M A | Hu, H | Katrich, V | Liu, W | Lu, Y | Manahan, D | Popov, P | Shui, W | Stevens, R C | Velasquez, J | Weierstall, U | White, K L | Zarzycka, B | Gpcr | Lcp | Membrane protein | Prostaglandin analogue | T4l | Xfel
