2KBC

Solution structure of human insulin-like peptide 5 (INSL5)

Summary for 2KBC

• Entry DOI: 10.2210/pdb2kbc/pdb
• Related: 2FHW 2K1V
• Descriptor: INSL5_B-chain, INSL5_A-chain (2 entities in total)
• Functional Keywords: peptide hormone, relaxin, insulin-like fold, hormone
• Biological source: synthetic construct; More
• Total number of polymer chains: 2
• Total formula weight: 5050.88

Authors

Rosengren, K.J.,Haugaard-Jonsson, L.M. (deposition date: 2008-11-25, release date: 2009-03-24, Last modification date: 2019-12-25)

Primary citation

Hossain, M.A.,Daly, N.L.,Craik, D.J.,Wade, J.D.,Rosengren, K.J.
Structure of human insulin-like peptide 5 and characterization of conserved hydrogen bonds and electrostatic interactions within the relaxin framework
Biochem.J., 419:619-627, 2009

PubMed Abstract: INSL5 (insulin-like peptide 5) is a two-chain peptide hormone related to insulin and relaxin. It was recently discovered through searches of expressed sequence tag databases and, although the full biological significance of INSL5 is still being elucidated, high expression in peripheral tissues such as the colon, as well as in the brain and hypothalamus, suggests roles in gut contractility and neuroendocrine signalling. INSL5 activates the relaxin family peptide receptor 4 with high potency and appears to be the endogenous ligand for this receptor, on the basis of overlapping expression profiles and their apparent co-evolution. In the present study, we have used solution-state NMR to characterize the three-dimensional structure of synthetic human INSL5. The structure reveals an insulin/relaxin-like fold with three helical segments that are braced by three disulfide bonds and enclose a hydrophobic core. Furthermore, we characterized in detail the hydrogen-bond network and electrostatic interactions between charged groups in INSL5 by NMR-monitored temperature and pH titrations and undertook a comprehensive structural comparison with other members of the relaxin family, thus identifying the conserved structural features of the relaxin fold. The B-chain helix, which is the primary receptor-binding site of the relaxins, is longer in INSL5 than in its close relative relaxin-3. As this feature results in a different positioning of the receptor-activation domain Arg(B23) and Trp(B24), it may be an important contributor to the difference in biological activity observed for these two peptides. Overall, the structural studies provide mechanistic insights into the receptor selectivity of this important family of hormones.

PubMed: 19178384
DOI: 10.1042/BJ20082353

Experimental method

SOLUTION NMR