Conformational analysis of possible biologically active (receptor-bound) conformations of peptides derived from cholecystokinin, cerulein and little gastrin and the opiate peptide, Met-enkephalin.
Possible biologically active (receptor-bound) conformations of peptides derived from cholecystokinin (CCK) have been deduced using conformational analysis combined with comparative studies of their biological specificities. Two peptides, the completely active carboxyl terminal heptapeptide from CCK (CCK-7), whose sequence is Tyr-Met-Gly-Trp-Met-Asp-Phe-NH2, and the carboxyl terminal heptapeptide from cerulein (CER-7) which has the same sequence as for CCK-7 except for replacement of Met 2 with a Thr 2, both stimulate peripheral receptors in gall bladder, pancreas, and pylorus in the gastrointestinal system. In contrast, two other very similar peptides, the last four residues of CCK (CCK-4) whose sequence is Trp-Met-Asp-Phe-NH2, and the carboxyl terminal hexapeptide of little gastrin (LGA-6, Tyr-Gly-Trp-Met-Asp-Phe-NH2, i.e., residue 2 deleted relative to CCK-7 and CER-7 sequences), interact specifically with gastrin receptors and not at all or very weakly with peripheral receptors. All of these peptides react with CCK receptors in the central nervous system, especially in forebrain. The results in the GI tract suggest that the peptides active on peripheral receptors adopt structures that are significantly different from those of the peptides that interact with gastrin receptors. We have generated all of the many low energy conformations for each of these peptides. By retaining only the conformations that are the same for peptides within the same group and then rejecting those resulting conformations that are the same for the peptides in the two different groups, we can greatly reduce the possible active conformations for the peptides within each class.(ABSTRACT TRUNCATED AT 250 WORDS)
Pincus
M R
MR
Department of Pathology, New York University Medical Center, NY 10016.
Murphy
R B
RB
Carty
R P
RP
Chen
J
J
Shah
D
D
Scheraga
H A
HA
D000595:Amino Acid Sequence; D002108:Ceruletide / Q000737:chemistry* / Q000378:metabolism; D002766:Cholecystokinin / Q000737:chemistry* / Q000378:metabolism; D004744:Enkephalin, Methionine / Q000737:chemistry* / Q000378:metabolism; D005755:Gastrins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000737:chemistry* / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D011949:Receptors, Cholecystokinin / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012844:Sincalide / Q000378:metabolism; D013758:Tetragastrin / Q000378:metabolism
D005755:Gastrins; D009479:Neuropeptides; D010446:Peptide Fragments; D010455:Peptides; D011949:Receptors, Cholecystokinin; D013758:Tetragastrin; C025997:cholecystokinin (27-33); C039260:gastrin hexapeptide; D004744:Enkephalin, Methionine; D002108:Ceruletide; D002766:Cholecystokinin; D012844:Sincalide