Structure, Function, and Engineering of Relaxin Hormones and Receptors

Abstract

The relaxin family peptide receptor 1 (RXFP1) and its agonist, relaxin-2, are of significant therapeutic interest in the areas of cardiovascular and fibrotic diseases. RXFP1 is a family A G protein-coupled receptor (GPCR), while relaxin-2 is a member of the insulin superfamily of peptide hormones. Many aspects of GPCR signaling have been well-defined, however, the mechanism of RXFP1 activation by relaxin-2 has remained enigmatic due to its unusual domain architecture. Our poor understanding of RXFP1’s function is largely attributable to the lack of structural information for the receptor, which has also hindered the development of RXFP1-targeted therapeutics. The work in this dissertation aims to investigate the molecular mechanism of RXFP1 signaling and contribute to the development of new RXFP1 agonists for therapeutic applications. In the studies presented here, we determined the active-state structure of RXFP1 using cryo-electron microscopy, revealing surprising details of the receptor’s signaling mechanism. We also generated an engineered relaxin-2 fusion protein with an extended serum half-life that maintains high biological activity at the RXFP1 receptor. Collectively, our work will advance therapeutic development for RXFP1 and relaxin-2, through engineering new properties into the native peptide hormone and facilitating the development of novel RXFP1 agonists through future structure-based drug design.