Mechanism of beta2AR regulation by an intracellular positive allosteric modulator.Liu, X., Masoudi, A., Kahsai, A.W., Huang, L.Y., Pani, B., Staus, D.P., Shim, P.J., Hirata, K., Simhal, R.K., Schwalb, A.M., Rambarat, P.K., Ahn, S., Lefkowitz, R.J., Kobilka, B.
(2019) Science 364: 1283-1287
- PubMed: 31249059
- DOI: https://doi.org/10.1126/science.aaw8981
- Primary Citation of Related Structures:
- PubMed Abstract:
Drugs targeting the orthosteric, primary binding site of G protein-coupled receptors are the most common therapeutics. Allosteric binding sites, elsewhere on the receptors, are less well-defined, and so less exploited clinically. We report the crystal structure of the prototypic β 2 -adrenergic receptor in complex with an orthosteric agonist and compound-6FA, a positive allosteric modulator of this receptor. It binds on the receptor's inner surface in a pocket created by intracellular loop 2 and transmembrane segments 3 and 4, stabilizing the loop in an α-helical conformation required to engage the G protein. Structural comparison explains the selectivity of the compound for β 2 - over the β 1 -adrenergic receptor. Diversity in location, mechanism, and selectivity of allosteric ligands provides potential to expand the range of receptor drugs.
Advanced Photon Technology Division, Research Infrastructure Group, SR Life Science Instrumentation Unit, RIKEN/SPring-8 Center, 1-1-1 Kouto Sayo-cho Sayo-gun, Hyogo 679-5148, Japan.