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Structural Consequences of Metal Complexation of cyclo [Pro‐Phe‐Phe‐Ala‐Xaa] 2 Decapeptides
Author(s) -
Saviano Gabriella,
Rossi Filomena,
Benedetti Ettore,
Pedone Carlo,
Mierke Dale F.,
Maione Annamaria,
Zanotti Giancarlo,
Tancredi Teodorico,
Saviano Michele
Publication year - 2001
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/1521-3765(20010316)7:6<1176::aid-chem1176>3.0.co;2-w
Subject(s) - antiparallel (mathematics) , chemistry , stereochemistry , peptide , hydrogen bond , crystallography , nuclear magnetic resonance spectroscopy , circular dichroism , gramicidin s , ligand (biochemistry) , gramicidin , molecule , receptor , biochemistry , organic chemistry , physics , quantum mechanics , membrane , magnetic field
The conformational features of both free and Ca 2+ ‐complexed cyclo [Pro‐Phe‐Phe‐Ala‐Xaa] 2 (with Xaa=Glu(OtBu), Lys(ClZ), Leu, and Ala) in solution have been determined by NMR spectroscopy and extensive distance–geometry calculations. The decapeptides are conformationally homogeneous in solution and show common structural features in their free and complexed forms. The structures of the free form contain only trans peptide bonds and are topologically similar to the structure of gramicidin‐S, folded up in two antiparallel extended structures, stabilized by interstrand hydrogen bonds, and closed at both ends by two β ‐turns. In contrast, the Ca 2+ ‐complexed peptides present two cis peptide bonds and are generally similar to those observed for the metal‐complexed forms of antamanide and related analogues, folded into a saddle shape with two β ‐turns. The Glu(OtBu)‐, Leu‐, and Lys(ClZ)‐containing peptides examined here maintain the biological activity of the cyclolinopeptide A in their ability to competitively inhibit cholate uptake. The natural antamanide and cyclolinopeptide A are both able to inhibit the uptake of bile salts into hepatocytes. They share the same postulated active sequence Pro‐Phe‐Phe. Based on our structural results, we conclude that the ability to adopt a global conformation, characterized by a clear amphipathic separation of hydrophobic and hydrophilic surfaces, is an important feature for the functioning of this class of peptides.