The 3D structure in pure water of endothelin-1, a recently discovered potent vasoconstrictor peptide, has been determined at different pH and temperatures, using two-dimensional 1H NMR spectroscopy and constrained molecular dynamics (MD). 170 Inter- and intra-residue NOE interactions were quantified as volume integrals and translated into distances. All the coupling constants between the amidic and the α-protons have been measured and several dihedral angles, thus obtained, have been used as constraints for the MD. Some stereospecific assignments have also been performed. A family of eleven structures, satisfying the distance constraints to within 0.3 Å, was obtained and showed that the C-terminal, determinant for the binding with the receptor, has a well defined conformation. The correlation time measurements gave an average molecular volume consistent with monomeric species. The tertiary structure at neutral pH is that of a compact molecule, in which the C-terminal of the peptide folds back toward the α-helical segment (residues 9–16), in close proximity to the pro-R methyl group of Val12, as defined by important NOEs involving residues 17–21 and the α-helical core residues 9–14. The results are in agreement with the deuterium exchange experiments, which confirm the existence of a hydrophobic region also at the site of the C-terminal residues 19–21.

Tertiary structure of endothelin-1 in water by 1H NMR and molecular dynamics studies / E. Ragg, R. Mondelli, S. Penco, G. Bolis, L. Baumer, A. Guaragna. - In: JOURNAL OF THE CHEMICAL SOCIETY. PERKIN TRANSACTIONS 2. - ISSN 1472-779X. - :6(1994 Jun), pp. 1317-1326.

Tertiary structure of endothelin-1 in water by 1H NMR and molecular dynamics studies

E. Ragg
Primo
;
R. Mondelli
Secondo
;
1994-06

Abstract

The 3D structure in pure water of endothelin-1, a recently discovered potent vasoconstrictor peptide, has been determined at different pH and temperatures, using two-dimensional 1H NMR spectroscopy and constrained molecular dynamics (MD). 170 Inter- and intra-residue NOE interactions were quantified as volume integrals and translated into distances. All the coupling constants between the amidic and the α-protons have been measured and several dihedral angles, thus obtained, have been used as constraints for the MD. Some stereospecific assignments have also been performed. A family of eleven structures, satisfying the distance constraints to within 0.3 Å, was obtained and showed that the C-terminal, determinant for the binding with the receptor, has a well defined conformation. The correlation time measurements gave an average molecular volume consistent with monomeric species. The tertiary structure at neutral pH is that of a compact molecule, in which the C-terminal of the peptide folds back toward the α-helical segment (residues 9–16), in close proximity to the pro-R methyl group of Val12, as defined by important NOEs involving residues 17–21 and the α-helical core residues 9–14. The results are in agreement with the deuterium exchange experiments, which confirm the existence of a hydrophobic region also at the site of the C-terminal residues 19–21.
endothelin-1 ; solution structure ; NMR ; Nuclear Overhauser Effect ; molecular dynamics
Settore CHIM/06 - Chimica Organica
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/178416
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