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Current Topics in Peptide & Protein Research   Volumes    Volume 3 
Structural investigation of a pro-region derived peptide substrate and an inhibitor of Proprotein Convertases PC1 and furin using NMR and molecular modeling studies
Ajoy Basak, Phan Viet Minh Tan, Hermann Dugas, Claude Lazure
Pages: 37 - 49
Number of pages: 13
Current Topics in Peptide & Protein Research
Volume 3 

Copyright © 1999 Research Trends. All rights reserved


The structures of two decapeptides, D-Tyr-Arg-Ser-Lys-Arg-Leu-Val-Gln-Lys-Asp (I) and D-Tyr-Arg-Ser-Lys-Arg-βCha-Val-Gln-Lys-Asp (II), which function respectively as a substrate and an inhibitor towards Proprotein Convertases (PC’s), PC1 and furin, were examined by various 2D NMR (nuclear magnetic resonance) spectroscopic methods. This includes COSY, ROESY, NOESY, HMBC (C13 vs H1) as well as temperature dependence studies of chemical shift of the amide protons. Analysis of the data was further accomplished by molecular modeling studies. These revealed that the substrate (I) and the inhibitor (II) possess a number of conformational similarities e.g. a possible β-turn at the P1-P1’ peptide bond. However there are some important structural differences between them that may provide a rationale for their distinct behavior towards Proprotein Convertases, PC1 and furin.

Thus in either analogs, the two carboxylic functions of terminal Asp residue are stabilized by potential H-bonding with the side chain residues of Arg5 and Lys9. The substrate (I) displayed a conformational preference with an inverse-β-turn structure consisting of a somewhat unusual 11-membered intra-molecular H-bonding. This leads to a more exposed P1-P1’ peptide bond (Arg5-CO-NH-Leu6) and a significant lack of stabilization of this bond. In contrast, the inhibitor, β-Cha analog (II) exhibited in its average conformation the presence of a β-turn structure containing a 10-membered intra-molecular H-bond. As a consequence, the amide carbonyl group between Arg5-β Cha6(P1-P1’) became strongly polarized by the electrostatic interactions with the side chain of Lys4 situated in close proximity. In these circumstances, the corresponding acyl-enzyme intermediate becomes stabilized by intramolecular H-bonding and resistant to the hydrolytic cleavage. Other important structural differences include the observation that, P1’Leu residue side chain in (I) is directed towards the interior of the molecule in contrast to (II) where P1’βCha residue side chain is projected to the exterior of the molecule, causing a more steric hindrance. Based on the NMR data in conjunction with molecular modelling studies, using Monte-Carlo conformational search, plausible three-dimensional structures were postulated for (I) and (II). The implications of such conformations in relationship to their interactions with PCs are discussed.
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