Unson C G, Wu C R, Merrifield R B
Rockefeller University, New York, New York 10021.
Biochemistry. 1994 Jun 7;33(22):6884-7. doi: 10.1021/bi00188a018.
The discovery of aspartic acid at position 9 in glucagon to be a critical residue for transduction has spurred renewed efforts to identify other strategic residues in the peptide sequence that dictate either receptor binding or biological activity. It also became apparent from further studies that Asp9 operates in conjunction with His1 in the activation mechanism that follows binding to the glucagon receptor. Indeed, it was later demonstrated that the protonatable histidine imidazole is important for transduction. It is likely that the interaction of a positively charged histidine 1 with a negatively charged aspartic acid 9 might be part of the triggering step at the molecular level. Two other aspartic acid residues in glucagon are capable of assuming a similar role, namely that of contributing to an electrostatic attraction with histidine via a negative carboxylate. These studies were conducted to investigate the role of aspartic acid 15 and 21 in glucagon action. Evidence reported here, gathered from 31 replacement analogs, supports the idea that in the absence of the requisite carboxyl group at position 9, histidine utilizes Asp21 or Asp15 as a compensatory site. Asp15 was also found to be indispensable for binding and may serve to tether the hormone to the receptor protein at the binding site. It is also demonstrated that these new findings promote the design of better glucagon antagonists.
胰高血糖素第9位天冬氨酸是转导的关键残基这一发现，促使人们重新努力在肽序列中识别出决定受体结合或生物活性的其他关键残基。进一步研究还表明，天冬氨酸9在与胰高血糖素受体结合后的激活机制中与组氨酸1协同作用。事实上，后来证明可质子化的组氨酸咪唑对转导很重要。带正电荷的组氨酸1与带负电荷的天冬氨酸9之间的相互作用可能是分子水平触发步骤的一部分。胰高血糖素中的另外两个天冬氨酸残基也能发挥类似作用，即通过负羧酸盐与组氨酸形成静电吸引。这些研究旨在探究天冬氨酸15和21在胰高血糖素作用中的作用。此处报道的证据来自31种替代类似物，支持了这样一种观点：在第9位缺乏必需羧基的情况下，组氨酸利用天冬氨酸21或天冬氨酸15作为补偿位点。还发现天冬氨酸15对于结合是不可或缺的，并且可能在结合位点将激素与受体蛋白拴系在一起。研究还表明，这些新发现促进了更好的胰高血糖素拮抗剂的设计。
