The biologically active conformations of a series of four
peptides [four
cholecystokinin (CCK)-related
peptides and
enkephalin] in their interactions with gastrointestinal receptors have been deduced using conformational computational analysis. The two
peptides that interact exclusively with peripheral-type
CCK receptors are the heptapeptide COOH-terminal fragment from CCK (CCK-7) and the analogous sequence from
cerulein (CER-7) in which
threonine replaces the
methionine proximal to the NH2 terminus. The two
peptides that interact exclusively with the
gastrin receptor in the stomach are the active COOH-terminal fragment of little
gastrin and the COOH-terminal tetrapeptide sequence common to all of these
peptides,
CCK-4. We find that preferred conformations for the peripherally active
peptides CCK-7 and CER-7 are principally beta-
bends, whereas little
gastrin and
CCK-4 are fundamentally helical. In the class of lowest energy structures for both
CCK-7 and CER-7, the aromatic rings of the
tyrosine and
phenylalanine lie close to one another whereas the
tryptophan indole ring points in the opposite direction. This structure is superimposable on the structures of a set of rigid indolyl
benzodiazepine derivatives that interact with complete specificity and high affinity with peripheral
CCK receptors further suggesting that the computed beta-
bends are the biologically active conformation. The biologically active conformation for
CCK-4 and the little
gastrin hexapeptide has also been deduced. By excluding conformations common to
CCK-7 and
CCK-4, which do not bond to each other's receptors, and then by selecting conformations in common to
CCK-4 and the
gastrin-related hexapeptide, which do bind to each other's receptors, we deduce that the biologically active conformation at the
gastrin receptor is partly helical and one in which the
indole of
tryptophan and the aromatic ring of
phenylalanine are close to one another while the
methionine and
aspartic acid side chains point in the opposite direction. These major differences in preferred structures between the common CCK-7/CER-7
peptides and the common CCK-4/little
gastrin peptides explain the mutually exclusive activities of these two sets of
peptides. We have observed that [
Met]enkephalin strongly antagonizes the action of the naturally occurring peripherally active
CCK-8 (CCK-7 with an NH2-terminal
aspartic acid residue added). The computed lowest energy structures for this
opiate peptide closely resemble key features of the computed CCK-7/CER-7 structure, further supporting the proposed structure.