The neuropeptide hormone relaxin-3 mediates its actions through activation of the relaxin-family peptide receptor-3 (RXFP3). Current evidence confirms an involvement of the RXFP3/relaxin-3 signalling system in the central regulation of feeding, arousal/sleep, emotional memory, and metabolism/neuroendocrine function. Thus RXFP3 represents a promising new target for various mental disorders. However the development of lead molecules for this receptor is non-trivial. Relaxin-3 is a large, complex, two-chain peptide and poorly selective for RXFP3 over related receptors. In addition any drug targeting RXFP3 is required to be able to pass the blood-brain barrier after systemic delivery, a considerable challenge. A detailed picture of how ligands interact with RXFP3 is therefore desirable for the rational design of novel analogues.
We have through extensive mutational efforts generated structure-activity relationships both for ligands and the receptor identifying key features of the interaction. These data have been used to generate models of the complex using the program package HADDOCK. Our data suggest that a recently developed single-chain antagonist, R3 B1-22R, which is a truncated variant of the relaxin-3 B-chain binds strikingly different to native relaxin-3. These data are highly relevant for the future development of this antagonist towards the clinic.