Determination of the core sequence of an antagonist of selectin-dependent leukocyte adhesion and correlation of its structure with molecular modeling studies.
The sequence 36-50 from the lectin domain of human P-selectin has been previously identified as a weak inhibitor of selectin-dependent leukocyte adhesion. A series of C- and N-terminally truncated peptides was synthesized to determine the limits of the active core region within the parent sequence. Deletions from both the N- and C-termini gave significant increases in inhibitory activity and identified 41-50 or 36-49 as minimum active sequences, but surprisingly not the common 41-49 peptide. All peptides tested showed parallel inhibition of both P- and E-selectin-dependent adhesion. A molecular model of the lectin domain was constructed using homology modeling. Examination of this model suggests one hypothesis to explain the increase in activity on deletion of Asp36.
Kruszynski
M
M
Centocor, Inc., Malvern, Pennsylvania 19355, USA.
Nakada
M T
MT
Tam
S H
SH
Taylor
A H
AH
Fieles
W E
WE
Heavner
G A
GA
D000595:Amino Acid Sequence; D002448:Cell Adhesion / Q000187:drug effects*; D019040:E-Selectin / Q000737:chemistry*; D006801:Humans; D019041:L-Selectin / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000502:physiology*; D019007:P-Selectin / Q000737:chemistry* / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology; D012091:Repetitive Sequences, Nucleic Acid
D019040:E-Selectin; D019007:P-Selectin; D010446:Peptide Fragments; D019041:L-Selectin