Structure of the complement C5a receptor bound to the extra-helical antagonist NDT9513727

The crystal structure of the complement receptor C5aR1 bound to a small-molecule antagonist provides insights into this receptor class and how they could be better targeted therapeutically. Structure of a complement receptor The complement system plays a central part in innate immune responses and provides a basic defence mechanism against infection. C5a is one component that is produced on activation of this system and is an inflammatory mediator that interacts with the G-protein-coupled receptor (GPCR) C5aR1. As such, C5aR1 inhibitors are anti-inflammatory targets for the treatment of sepsis, psoriasis and rheumatoid arthritis. Fiona Marshall and colleagues report the crystal structure of the complement C5a receptor bound to a small-molecule antagonist. These findings offer molecular-level insights into this class of receptors and how they could be better targeted therapeutically. As with some other recently reported GPCR structures, the ligand binds to an allosteric binding pocket outside the transmembrane bundle. This work also explains the difference in pharmacology between human and rodent receptors. The complement system is a crucial component of the host response to infection and tissue damage. Activation of the complement cascade generates anaphylatoxins including C5a and C3a. C5a exerts a pro-inflammatory effect via the G-protein-coupled receptor C5a anaphylatoxin chemotactic receptor 1 (C5aR1, also known as CD88) that is expressed on cells of myeloid origin 1 , 2 . Inhibitors of the complement system have long been of interest as potential drugs for the treatment of diseases such as sepsis, rheumatoid arthritis, Crohn’s disease and ischaemia-reperfusion injuries 1 . More recently, a role of C5a in neurodegenerative conditions such as Alzheimer’s disease has been identified 3 . Peptide antagonists based on the C5a ligand have progressed to phase 2 trials in psoriasis and rheumatoid arthritis; however, these compounds exhibited problems with off-target activity, production costs, potential immunogenicity and poor oral bioavailability. Several small-molecule competitive antagonists for C5aR1, such as W-54011 5 and NDT9513727 6 , have been identified by C5a radioligand-binding assays 4 . NDT9513727 is a non-peptide inverse agonist of C5aR1, and is highly selective for the primate and gerbil receptors over those of other species. Here, to study the mechanism of action of C5a antagonists, we determine the structure of a thermostabilized C5aR1 (known a