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|2h8b, 20 NMR models ()|
Solution structure of INSL3
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.
Solution structure and characterization of the LGR8 receptor binding surface of insulin-like peptide 3., Rosengren KJ, Zhang S, Lin F, Daly NL, Scott DJ, Hughes RA, Bathgate RA, Craik DJ, Wade JD, J Biol Chem. 2006 Sep 22;281(38):28287-95. Epub 2006 Jul 25. PMID:16867980
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[INSL3_HUMAN] Defects in INSL3 seems to be a cause of cryptorchidism (CRYPTO) [MIM:219050]; also known as impaired testicular descent. It is one of the most frequent congenital abnormalities in humans, involving 2-5% of male births. Cryptorchidism is associated with increased risk of infertility and testicular cancer. The frequency of INSL3 gene mutations as a cause of cryptorchidism is low.
[INSL3_HUMAN] Seems to play a role in testicular function. May be a trophic hormone with a role in testicular descent in fetal life. Is a ligand for LGR8 receptor.
About this Structure
2h8b is a 2 chain structure. Full experimental information is available from OCA.
- Rosengren KJ, Zhang S, Lin F, Daly NL, Scott DJ, Hughes RA, Bathgate RA, Craik DJ, Wade JD. Solution structure and characterization of the LGR8 receptor binding surface of insulin-like peptide 3. J Biol Chem. 2006 Sep 22;281(38):28287-95. Epub 2006 Jul 25. PMID:16867980 doi:10.1074/jbc.M603829200
- ↑ Tomboc M, Lee PA, Mitwally MF, Schneck FX, Bellinger M, Witchel SF. Insulin-like 3/relaxin-like factor gene mutations are associated with cryptorchidism. J Clin Endocrinol Metab. 2000 Nov;85(11):4013-8. PMID:11095425
- ↑ Marin P, Ferlin A, Moro E, Rossi A, Bartoloni L, Rossato M, Foresta C. Novel insulin-like 3 (INSL3) gene mutation associated with human cryptorchidism. Am J Med Genet. 2001 Nov 1;103(4):348-9. PMID:11746019
- ↑ Canto P, Escudero I, Soderlund D, Nishimura E, Carranza-Lira S, Gutierrez J, Nava A, Mendez JP. A novel mutation of the insulin-like 3 gene in patients with cryptorchidism. J Hum Genet. 2003;48(2):86-90. PMID:12601553 doi:10.1007/s100380300012