The conformational features of human melanin-concentrating hormone (hMCH) [Asp 1-Phe2-Asp3-Met4-Leu-Arg6-cyclo- (S-S)(Cys7-Met8-Leu9-Gly10-Arg11-Val12-Tyr13-Arg14-Pro15- Cys16)-Trp17-Gln18-Val19], in water and in a CD3CN/H2O (1:1 v/v) mixture at 298 K, have been determined by NMR spectroscopy followed by simulated annealing and molecular dynamics analyses to identify conformer populations. Backbone clustering analysis of NMR-spectroscopy-derived structures in the 7-16 peptide region led to the identification of a single representative structure in each solvent. Both root mean square deviation clustering and secondary structure analysis of the final conformers in both solvents show substantial convergence of most conformers into a single fold in the 4-17 region, with a limited variability around Gly10 and Tyr13 on going from CD3CN/H2O to pure water. The main feature deduced from the analysis of secondary structures is the occurrence of an N-terminal α helix of variable length, which spans an overall residue range of 2-9. A comparative analysis in the two solvents highlights that these structures are substantially different from that reported in the literature for the cyclic MCH(5-14) subunit of salmon MCH, which was used to perform a molecular characterization of the MCH/receptor complex. Our conformational data call for a critical revision of the proposed MCH/receptor complex model.
Conformational features of human melanin-concentrating hormone: An NMR and computational analysis
FATTORUSSO, Roberto;ISERNIA, Carla;
2003
Abstract
The conformational features of human melanin-concentrating hormone (hMCH) [Asp 1-Phe2-Asp3-Met4-Leu-Arg6-cyclo- (S-S)(Cys7-Met8-Leu9-Gly10-Arg11-Val12-Tyr13-Arg14-Pro15- Cys16)-Trp17-Gln18-Val19], in water and in a CD3CN/H2O (1:1 v/v) mixture at 298 K, have been determined by NMR spectroscopy followed by simulated annealing and molecular dynamics analyses to identify conformer populations. Backbone clustering analysis of NMR-spectroscopy-derived structures in the 7-16 peptide region led to the identification of a single representative structure in each solvent. Both root mean square deviation clustering and secondary structure analysis of the final conformers in both solvents show substantial convergence of most conformers into a single fold in the 4-17 region, with a limited variability around Gly10 and Tyr13 on going from CD3CN/H2O to pure water. The main feature deduced from the analysis of secondary structures is the occurrence of an N-terminal α helix of variable length, which spans an overall residue range of 2-9. A comparative analysis in the two solvents highlights that these structures are substantially different from that reported in the literature for the cyclic MCH(5-14) subunit of salmon MCH, which was used to perform a molecular characterization of the MCH/receptor complex. Our conformational data call for a critical revision of the proposed MCH/receptor complex model.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
