OX2R
January 2022
Orexin type 2 receptor
In the last 15 years, the orexin type 2 receptor (OX2R) has emerged as an interesting drug target for narcolepsy type 1 (NT1) – a chronic neurological disorder characterized by excessive daytime sleepiness and sudden loss of muscle tone (cataplexy), currently without a cure.
OX2R is a class A (rhodopsin-like) G protein-coupled receptor (GPCR) that binds the excitatory neuropeptides Orexin-A (OxA) and Orexin-B (OxB). This interaction triggers a cascade of reactions that control sleep and wakefulness. Extremely low levels of orexins due to the loss of orexin-producing neurons disrupt the orexin signaling and cause NT1.
Unfortunately, the available therapeutics address only the symptoms in narcoleptic patients and have substantial side effects. A more efficient way of treating the disorder would be to boost the activity of OX2R using selective small-molecule agonists, but their identification has been proven difficult.
However, scientists at Merck&Co made a big step towards this goal by successfully determining the first structures of OX2R in an active state. Using the single-particle cryo-EM technique, they revealed the structures of OX2R in complex with two agonists – the endogenous peptide OxB and a small-molecule ligand (compound 1) (PDB IDs: 7L1U and 7L1V). These structures thus help us understand the OX2R activation mechanism which will further support the rational structure-based design of agonists.
Another interesting finding from the article is the unexpected conformational change of the endogenous peptide OxB upon binding.
Image:The comparison of the Orexin B in the non-bound (left) and receptor-bound (right) conformation. The C-terminal portion (N20-M28) of the OxB extends upon binding deep into the OX2R transmembrane core.
A previously resolved NMR structure of the isolated peptide (PDB ID: 1CQ0) shows that OxB folds into two alpha-helices oriented perpendicular to each other (image left). However, when binding to OX2R, the C-terminal portion of the peptide adopts an extended conformation that reaches all down to the bottom of the orthosteric site, thus stabilizing the active state of the receptor (image right).
This kind of conformational change is difficult to predict with today’s tools and the newly published OxB-OX2R structure, therefore, brings valuable structural insights.
Bonus: The registration, visualization and analysis of peptides-protein interactions will soon be available in 3decision thanks to the addition of software components from ChemAxon. Read more about our collaboration here.