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Titolo:
Type I beta-turn conformation is important for biological activity of the melanocyte-stimulating hormone analogues
Autore:
Li, SZ; Lee, JH; Lee, W; Yoon, CJ; Baik, JH; Lim, SK;
Indirizzi:
Yonsei Univ, Coll Med, Dept Internal Med, Div Endocrinol, Seoul, South Korea Yonsei Univ Seoul South Korea l Med, Div Endocrinol, Seoul, South Korea Yonsei Univ, Coll Sci, Dept Biochem, Seoul 120749, South Korea Yonsei Univ Seoul South Korea 120749 Biochem, Seoul 120749, South Korea Catholic Univ, Coll Sci, Dept Chem, Seoul, South Korea Catholic Univ Seoul South Korea Coll Sci, Dept Chem, Seoul, South Korea Yonsei Univ, Coll Med, Clin Res Ctr, Seoul, South Korea Yonsei Univ Seoul South Korea oll Med, Clin Res Ctr, Seoul, South Korea
Titolo Testata:
EUROPEAN JOURNAL OF BIOCHEMISTRY
fascicolo: 1, volume: 265, anno: 1999,
pagine: 430 - 440
SICI:
0014-2956(199910)265:1<430:TIBCII>2.0.ZU;2-C
Fonte:
ISI
Lingua:
ENG
Soggetto:
MELANOCORTIN RECEPTOR SUBTYPES; SIMULATED ANNEALING CALCULATIONS; 2-DIMENSIONAL NMR-SPECTROSCOPY; AGOUTI OBESITY SYNDROME; MOLECULAR-CLONING; 3-DIMENSIONAL STRUCTURES; RADIOLIGAND BINDING; ALPHA-MELANOTROPIN; H-1-NMR SPECTRA; NEUROPEPTIDE-Y;
Keywords:
melanocortin; melanocyte-stimulating hormone receptor; NMR; receptor-binding and cAMP-generating activity; type I beta-turn;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
42
Recensione:
Indirizzi per estratti:
Indirizzo: Lim, SK Yonsei Univ, Coll Med, Dept Internal Med, Div Endocrinol, Seoul, South Korea Yonsei Univ Seoul South Korea iv Endocrinol, Seoul, South Korea
Citazione:
S.Z. Li et al., "Type I beta-turn conformation is important for biological activity of the melanocyte-stimulating hormone analogues", EUR J BIOCH, 265(1), 1999, pp. 430-440

Abstract

In order to define which structure of alpha-melanocyte-stimulating hormone(MSH) analogues plays a critical role for ligand-receptor interaction and selectivity, we analysed receptor-binding and cAMP-generating activity in Chinese hamster ovary cell lines stably transfected with rMC3R and hMC4R, aswell as the NMR structures of chemically synthesized alpha-MSH analogues. Compared with [Ahx4]alpha-MSH, the linear MTII designated as alpha-MSH-ND revealed a preference for the MC4R, whereas its IC50 and EC50 values were comparable to those of MTII reported previously. Truncation of Ahx4 and Asp5 of alpha-MSH-ND remarkably decreased the receptor-binding and cAMP-generating activity. Meanwhile, maximum cAMP-generating activity was observed at a higher concentration (10(-5) M) of alpha-MSH-ND(6-10), and MC4R preference was changed into MC3R preference. In contrast, [Gln6]alpha-MSH-ND(6-10) lost its cAMP-generating activity almost completely, even though it bound to both receptors. Whereas the solution conformation of alpha-MSH-ND revealed astable type I beta-turn structure, [Gln6]alpha-MSH-ND(6-10) revealed a tight gamma-turn composed of Gln6-D-Phe7-Arg8. Replacement of the His6 residueof alpha-MSH-ND by Gln, Asn, Arg or Lys decreased not only the receptor binding, but also the cAMP-generating activity in both the MC3R and the MC4R. The structure of [Gln6]alpha-MSH-ND exhibited a stable type I' beta-turn comprising Asp5, Gln6, D-Phe7 and Arg8. [Lys6]alpha-MSH-ND showed a greatly reduced binding affinity and cAMP-generating activity with the loss of MC4Rselectivity. In NMR studies, [Lys6]alpha-MSH-ND also demonstrated a gamma-turn conformation around Lys6-DPhe7-Arg8. From the above results, we conclude that a type I beta-turn conformation comprising the residues Asp5-His6-(D-Phe7)-Arg8 was important for receptor binding and activation, as well as the selectivity of MSH analogues.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 04/07/20 alle ore 05:27:21