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Structure of the human insulin-like peptide 5 and characterization of conserved hydrogen bonds and electrostatic interactions within the relaxin framework
University of Kalmar, School of Pure and Applied Natural Sciences. (BBCL)ORCID iD: 0000-0003-0113-6535
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2009 (English)In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 419, p. 619-627Article in journal (Refereed) Published
Abstract [en]

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 fulfil 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. 

Place, publisher, year, edition, pages
2009. Vol. 419, p. 619-627
National Category
Organic Chemistry
Research subject
Chemistry, Organic Chemistry
Identifiers
URN: urn:nbn:se:lnu:diva-1953DOI: 10.1042/BJ20082353OAI: oai:DiVA.org:lnu-1953DiVA, id: diva2:309001
Available from: 2010-04-06 Created: 2010-04-06 Last updated: 2017-04-18Bibliographically approved
In thesis
1. Structure and function of relaxins
Open this publication in new window or tab >>Structure and function of relaxins
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The relaxin/insulin superfamily is a group of peptide hormones that consists of ten members in human, namely relaxins 1-3, insulin-like peptides (INSL) 3-6, insulin and insulin-like growth factors (IGF) I-II. These peptides have various functions in the body, such as regulating growth, blood glucose levels,  collagen metabolism, germ cell maturation and appetite. Misregulation of these mechanisms is associated with disease and accordingly they are of interest as potential pharmaceutical targets. Structurally the hormones are characterised by two peptide chains, A and B, which are held together by one intra A-chain and two inter chain disulfide bonds. Four different G-protein coupled receptors (GPCR) called relaxin family peptide receptor (RXFP) 1-4 have been found to respond to stimuli by different relaxin peptides. RXFP3 and RXFP4 are classic peptide ligand GPCRs, whereas RXFP1 and RXFP2 are characterised by a large extracellular leucine rich-repeat domain. Relaxin-3, which is the relaxin family ancestor, is the only relaxin peptide known to be able to bind and activate both subtypes of GPCRs, namely RXFP1, RXFP3 and RXFP4.

The aim of this thesis was to analyse the structure-function relationship of the relaxin ligands and receptors, and to use this information to develop selective ligands for the relaxin receptors, which can be used as drug leads or pharmacological tools for investigating the physiological roles of the RXFPs.

The 3D structures of native INSL5 and relaxin-2 were determined by solution NMR spectroscopy. The peptides showed an insulin/relaxin-like overall fold. A relaxin chimera peptide, consisting of the A-chain from INSL5 and the B-chain from relaxin-3, R3/I5, which has been shown to be selective for RXFP3 and RXFP4 over RXFP1, was also subjected to NMR studies. The R3/I5 peptide maintained an insulin/relaxin-like overall fold, and the relaxin-3 B-chain adopted a conformation identical to that in native relaxin-3, confirming that the activity of R3/I5 can be directly related to its primary sequence. Furthermore, a truncation study was undertaken to ascertain the importance of the termini for structure and function. By using the knowledge generated from the structure-function relationship, a single-chain high affinity RXFP3 selective antagonist was developed.

In conclusion, this thesis has contributed to broaden the knowledge of the structure-function relationship of the relaxin ligands and the development of a selective RXFP3 antagonist, which is currently a drug lead for treatment of neurological disorders including stress and obesity.

Place, publisher, year, edition, pages
Växjö, Kalmar: Linneaus University Press, 2011
Series
Linnaeus University Dissertations ; 31/2011
Keywords
relaxin, insulin-like peptide, peptide hormone, peptide synthesis and NMR
National Category
Organic Chemistry
Research subject
Chemistry, Organic Chemistry
Identifiers
urn:nbn:se:lnu:diva-9793 (URN)978-91-86491-55-0 (ISBN)
Public defence
2011-01-28, N2007, Smålandsgatan 26B, Kalmar, 09:30 (English)
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Supervisors
Available from: 2010-12-21 Created: 2010-12-21 Last updated: 2017-04-18Bibliographically approved

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Haugaard-Kedström (published under the name Haugaard-Jönsson), Linda M.Rosengren, K. Johan

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