Solution Structure and Novel Insights into the Determinants of the Receptor Specificity of Human Relaxin-3

• Published in: The Journal of biological chemistry Vol. 281; no. 9; pp. 5845 - 5851
• Main Authors: Rosengren, K. Johan, Lin, Feng, Bathgate, Ross A.D., Tregear, Geoffrey W., Daly, Norelle L., Wade, John D., Craik, David J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.03.2006; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Sequence; Animals; Binding Sites; Cell Line; Cyclic AMP - metabolism; Female; Humans; Models, Molecular; Molecular Sequence Data; Nuclear Magnetic Resonance, Biomolecular; Pregnancy; Protein Folding; Protein Structure, Secondary; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - metabolism; Relaxin - chemistry; Relaxin - genetics; Relaxin - metabolism; Sequence Alignment
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M511210200

Relaxin-3 is the most recently discovered member of the relaxin family of peptide hormones. In contrast to relaxin-1 and -2, whose main functions are associated with pregnancy, relaxin-3 is involved in neuropeptide signaling in the brain. Here, we report the solution structure of human relaxin-3, the first structure of a relaxin family member to be solved by NMR methods. Overall, relaxin-3 adopts an insulin-like fold, but the structure differs crucially from the crystal structure of human relaxin-2 near the B-chain terminus. In particular, the B-chain C terminus folds back, allowing TrpB27 to interact with the hydrophobic core. This interaction partly blocks the conserved RXXXRXXI motif identified as a determinant for the interaction with the relaxin receptor LGR7 and may account for the lower affinity of relaxin-3 relative to relaxin for this receptor. This structural feature is likely important for the activation of its endogenous receptor, GPCR135.