Inhibition of homotypic adhesion of T-cells: secondary structure of an ICAM-1-derived cyclic peptide.
The objective of this study was to elucidate the solution conformation of cyclo-(1,12) Pen1-Pro2-Ser3-Lys4-Val5-Ile6-Leu7-Pro8-Ar g9-Gly10-Gly11-Cys12 (1) derived from the intercellular adhesion molecule-1 (ICAM-1). Cyclic peptide 1 inhibits homotypic adhesion of T-cells (Molt-3) mediated by ICAM-1 and the leukocyte function-associated antigen-1 (LFA-1) on the surface of T-cells. Cyclic peptide 1 is more potent than is the linear peptide Pen1-Pro2-Ser3-Lys4-Val5-Ile6-Leu7-Pro8-Ar g9-Gly10-Gly11-Cys12 (2) in inhibiting homotypic adhesion. The difference in biological activity of peptides 1 and 2 may be due to the more stable conformation of cyclic peptide 1 compared to linear peptide 2 or because cyclization prevents the peptide from adopting non-productive conformation. Therefore, conformational studies of cyclic peptide 1 will give a better understanding of its biological active conformation. The conformational studies of cyclic peptide 1 were done by NMR, CD and molecular dynamics simulations. NMR studies indicated that the major conformation of cyclic peptide 1 contained trans-configuration at both X-Pro peptide bonds. Type I beta-turns at Lys4-Val5-Ile6-Leu7 and Leu7-Pro8-Arg9-Gly10 were found in cyclic peptide 1. The C- and N-terminal regions of this peptide were stabilized by antiparallel beta-sheet-like structure with the presence of intramolecular hydrogen bonds. The overall structure of this peptide exposed the hydrophobic side chains on one face of the molecule and the hydrophilic side chains on the other.
Jois
D S
DS
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, USA.
Pal
D
D
Tibbetts
S A
SA
Chan
M A
MA
Benedict
S H
SH
Siahaan
T J
TJ
D000595:Amino Acid Sequence; D002448:Cell Adhesion / Q000187:drug effects*; D002942:Circular Dichroism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D010456:Peptides, Cyclic; D018799:Intercellular Adhesion Molecule-1