Relaxin-3 is a highly conserved neuropeptide, which through interactions with its receptor relaxin-family peptide receptor-3 (RXFP3) mediates important physiological signalling involved in the control of of feeding, stress, sleep and memory. Consequently RXFP3 represents a potential novel pharmaceutical target for mental disorders and weight control.
Realxin-3 is a member of the insulin/relaxin family of peptide hormones, comprising a two-chain structure braced by three disulfide bonds. Extensive structure-activity relationship have highlighted that the key interaction sites of relaxin-3 are located in the B-chain. On the basis of this we developed a single chain peptide antagonist for RXFP3, capable of blocking RXFP3 in vivo and modulating food intake and addictive behaviour in rodents.
Targeting this receptor pharmacologically represents a significant challenge given that a drug would have to be able to enter the CNS. Thus further minimisation and stabilisation of the single chain lead peptide is required. To address this we have undertaken extensive mutational experiments on the ligand and receptor to create a model of the complex. We show that the binding site involves part of the relaxin-3 binding site but also additional features specific to the smaller more flexible single chain ligand.