While the past 10 years have seen great advances in our knowledge of GPCR structures peptide GPCRs, especially those with large structured ectodomains (ECDs), remain poorly understood. This is mainly because the flexibility of linkers joining the ECDs to the transmembrane domains (TMDs) impedes crystallization. Hence the study of complex peptide receptors requires different approaches. The peptide hormone relaxin activates the GPCR relaxin family peptide 1 (RXFP1) receptor (previously LGR7). RXFP1 is of considerable therapeutic interest as relaxin has successfully completed a phase III clinical trial for the treatment of acute heart failure. RXFP1 contains a large ECD which is composed of an N-terminal LDLa module connected to a leucine rich-repeat (LRRs) domain by a “linker” region with a further linker connecting the LRR and TMD. Studies using peptide and receptor mutants have provided a basic understanding of the binding and activation mechanism. Relaxin binds with high affinity to the ECD, requiring both the LRR domain and the linker between the LRRs and the LDLa module, and with low affinity to the TMD. However receptor signalling absolutely requires the LDLa module which may act as a tethered agonist to drive relaxin mediated receptor activation. To obtain more detailed structures of the interaction of relaxin and the LDLa module with the receptor domains and the structural rearrangements associated with LDLa mediated activation we have divided the RXFP1 protein into smaller segments for bacterial recombinant expression and NMR based interaction analysis. This approach has enabled the mapping of critical low affinity binding interactions in the ECD and TMD and the determination of conformational changes in the LRR-LDLa linker that are essential to orient the LDLa to interact with the RXFP1 TMD. This presentation will discuss the unique challenges of structure based drug design for complex peptide GPCR targets like RXFP1.