Solution structure and characterization of the LGR8 receptor binding surface of insulin-like peptide 3

Rosengren, K. J., Zhang, S., Lin, F., Daly, N. L., Scott, D. J., Hughes, R. A., Bathgate, R. A. D., Craik, D. J. and Wade, J. D. (2006) Solution structure and characterization of the LGR8 receptor binding surface of insulin-like peptide 3. Journal of Biological Chemistry, 281 38: 28287-28295. doi:10.1074/jbc.M603829200

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Author Rosengren, K. J.
Zhang, S.
Lin, F.
Daly, N. L.
Scott, D. J.
Hughes, R. A.
Bathgate, R. A. D.
Craik, D. J.
Wade, J. D.
Title Solution structure and characterization of the LGR8 receptor binding surface of insulin-like peptide 3
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2006-07-25
Sub-type Article (original research)
DOI 10.1074/jbc.M603829200
Open Access Status File (Publisher version)
Volume 281
Issue 38
Start page 28287
End page 28295
Total pages 9
Editor Herbert Tabor
Place of publication Bethesda
Publisher American Society for Biochemistry Molecular Biology Inc
Collection year 2006
Language eng
Subject C1
250302 Biological and Medical Chemistry
780105 Biological sciences
Abstract Insulin-like peptide 3 (INSL3), a member of the relaxin peptide family, is produced in testicular Leydig cells and ovarian thecal cells. Gene knock-out experiments have identified a key biological role in initiating testes descent during fetal development. Additionally, INSL3 has an important function in mediating male and female germ cell function. These actions are elicited via its recently identified receptor, LGR8, a member of the leucine-rich repeat-containing G-protein- coupled receptor family. To identify the structural features that are responsible for the interaction of INSL3 with its receptor, its solution structure was determined by NMR spectroscopy together with in vitro assays of a series of B-chain alanine-substituted analogs. Synthetic human INSL3 was found to adopt a characteristic relaxin/ insulin-like fold in solution but is a highly dynamic molecule. The four termini of this two-chain peptide are disordered, and additional conformational exchange is evident in the molecular core. Alanine-substituted analogs were used to identify the key residues of INSL3 that are responsible for the interaction with the ectodomain of LGR8. These include Arg(B16) and Val(B19), with His(B12) and Arg(B20) playing a secondary role, as evident from the synergistic effect on the activity in double and triple mutants involving these residues. Together, these amino acids combine with the previously identified critical residue, Trp(B27), to form the receptor binding surface. The current results provide clear direction for the design of novel specific agonists and antagonists of this receptor.
Keyword Biochemistry
Molecular Biology
Biochemistry & Molecular Biology
Relaxin-like Factor
Q-Index Code C1

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Created: Wed, 15 Aug 2007, 09:14:40 EST