Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01350 (gastrin)
 9,683 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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)
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PMID:Conformational analysis of possible biologically active (receptor-bound) conformations of peptides derived from cholecystokinin, cerulein and little gastrin and the opiate peptide, Met-enkephalin. 285 38

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.
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PMID:On the biologically active structures of cholecystokinin, little gastrin, and enkephalin in the gastrointestinal system. 303 25