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J. Biol. Chem., Vol. 281, Issue 9, 5845-5851, March 3, 2006

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

K. Johan Rosengren, Feng Lin^¶, Ross A. D. Bathgate^¶, Geoffrey W. Tregear^¶, Norelle L. Daly, John D. Wade^¶, and David J. Craik¹

From the Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia, the ^¶Howard Florey Institute, University of Melbourne, Victoria 3010, Australia, and the Department of Chemistry and Biomedical Sciences, University of Kalmar, SE-392 81 Kalmar, Sweden

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 Trp^B27 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.

Received for publication, October 14, 2005 , and in revised form, December 12, 2005.

^* This work was supported in part by National Health and Medical Research Council Project Grants 350284 (to J. D. W.) and 300012 (to R. A. D. B. and J. D. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Australian Research Council Professorial Fellow. To whom correspondence should be addressed. Tel.: 61-7-3346-2019; Fax: 61-7-3346-2029; E-mail: d.craik{at}imb.uq.edu.au.

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