Pincus M R, Murphy R B, Carty R P, Chen J, Shah D, Scheraga H A
Department of Pathology, New York University Medical Center, NY 10016.
Peptides. 1988;9 Suppl 1:145-52. doi: 10.1016/0196-9781(88)90238-0.
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)
通过构象分析并结合对其生物学特异性的比较研究，已推导出去胆囊收缩素（CCK）衍生肽可能的生物活性（受体结合）构象。两种肽，即来自CCK的完全活性羧基末端七肽（CCK - 7），其序列为Tyr - Met - Gly - Trp - Met - Asp - Phe - NH₂，以及来自蛙皮素的羧基末端七肽（CER - 7），其序列与CCK - 7相同，只是第2位的Met被Thr取代，二者均刺激胃肠道系统中胆囊、胰腺和幽门的外周受体。相比之下，另外两种非常相似的肽，CCK的最后四个残基（CCK - 4），其序列为Trp - Met - Asp - Phe - NH₂，以及小胃泌素的羧基末端六肽（LGA - 6，Tyr - Gly - Trp - Met - Asp - Phe - NH₂，即相对于CCK - 7和CER - 7序列缺失第2位残基），与胃泌素受体特异性相互作用，而与外周受体完全不相互作用或相互作用非常弱。所有这些肽都与中枢神经系统中的CCK受体反应，尤其是在前脑。胃肠道中的结果表明，作用于外周受体的肽所采用的结构与与胃泌素受体相互作用的肽的结构有显著差异。我们已为每种肽生成了所有许多低能量构象。通过仅保留同一组内肽相同的构象，然后舍弃两个不同组中肽相同的那些所得构象，我们可以大大减少每类肽可能的活性构象。（摘要截短于250字）
