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The first 3D structure of a full-length G-protein-coupled receptor whose natural activator is unknown has been determined, providing insights into an unusual mode of activation and a basis for discovering therapeutics.
G-protein-coupled receptors are the largest class of membrane protein in the human genome, and represent the most abundant pharmaceutical targets. More than 800 such receptors are known in humans, of which perhaps 100 are orphan receptors — those for which the naturally occurring (endogenous) ligand molecules that bind to and activate them have yet to be identified1,2. This lack of understanding of orphan G-protein-coupled receptors (oGPCRs) impedes our ability to exploit their potential as therapeutic targets. Writing in Nature, Lin et al.3 close this gap in knowledge by reporting the first 3D structure of a full-length oGPCR, GPR52, in multiple states.