...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Biochemistry >The glycine residue in cyclic lactam analogues of galanin(1-16)-NH2 is important for stabilizing an N-terminal helix.
【24h】

The glycine residue in cyclic lactam analogues of galanin(1-16)-NH2 is important for stabilizing an N-terminal helix.

机译：甘丙肽（1-16）-NH2的环状内酰胺类似物中的甘氨酸残基对于稳定N末端螺旋很重要。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The neuropeptide galanin is a 29- or 30-residue peptide whose physiological functions are mediated by G-protein-coupled receptors. Galanin's agonist activity has been shown to be associated with the N-terminal sequence, galanin(1-16). Conformational investigations previously carried out on full-length galanin have, furthermore, indicated the presence of a helical conformation in the neuropeptide's N-terminal domain. Several cyclic lactam analogues of galanin(1-16)-NH2 were prepared in an attempt to stabilize an N-terminal helix in the peptide. Here we describe and compare the solution conformational properties of these analogues in the presence of SDS micelles as determined by NMR, CD, and fluorescence spectroscopy. Differences in CD spectral profiles were observed among the compounds that were studied. Both c[D4, K8]Gal(1-16)-NH2 and c[D4,K8]Gal(1-12)-NH2 adopted stable helical conformations in the micelle solution. On the basis of the analyses of their respective alpha H chemical shifts and NOE patterns, this helix was localized to the first 10 residues. The distance between the aromatic rings of Trp2 and Tyr9 in c[D4, K8]Gal(1-16)-NH2 was determined to be 10.8 +/- 3 A from fluorescence resonance energy transfer measurements. This interchromophore spacing was found to be more consistent with a helical structure than an extended one. Removal of the Gly1 residue in compounds c[D4,K8]Gal(1-16)-NH2 and c[D4, K8]Gal(1-12)-NH2 resulted in a loss of helical conformation and a concomitant reduction in binding potency at the GalR1 receptor but not at the GalR2 receptor. The nuclear Overhauser enhancements obtained for the Gly1 deficient analogues did, however, reveal the presence of nascent helical structures within the N-terminal sequence. Decreasing the ring structure size in c[D4, K8]Gal(1-16)-NH2 by replacing Lys8 with an ornithine residue or by changing the position of the single lysine residue from eight to seven was accompanied by a complete loss of helical structure and dramatically reduced receptor affinity. It is concluded from the data obtained for the series of cyclic galanin(1-16)-NH2 analogues that both the ring structure size and the presence of an N-terminal glycine residue are important for stabilizing an N-terminal helix in these compounds. However, although an N-terminal helix constitutes a predominant portion of the conformational ensemble for compounds c[D4,K8]Gal(1-16)-NH2 and c[D4, K8]Gal(1-12)-NH2, these peptides nevertheless are able to adopt other conformations in solution. Consequently, the correlation between the ability of the cyclic galanin analogues to adopt an N-terminal helix and bind to the GalR1 receptor may be considered as a working hypothesis.
机译：神经肽甘丙肽是29或30个残基的肽，其生理功能由G蛋白偶联受体介导。已证明甘丙肽的激动剂活性与N末端序列甘丙肽（1-16）有关。此外，先前对全长甘丙肽进行的构象研究还表明，神经肽的N末端结构域中存在螺旋构象。制备了几种甘丙肽（1-16）-NH2的环状内酰胺类似物，以稳定肽中的N末端螺旋。在这里我们描述和比较在SDS胶束存在下这些类似物的溶液构象性质，如NMR，CD和荧光光谱法所确定。在所研究的化合物之间观察到CD光谱图的差异。 c [D4，K8] Gal（1-16）-NH2和c [D4，K8] Gal（1-12）-NH2在胶束溶液中均采用稳定的螺旋构象。根据对它们各自的αH化学位移和NOE模式的分析，该螺旋被定位在前10个残基上。根据荧光共振能量转移测量，在c [D4，K8] Gal（1-16）-NH2中，Trp2和Tyr9的芳香环之间的距离确定为10.8 +/- 3A。发现发色团之间的间距与螺旋结构相比于扩展的结构更一致。化合物c [D4，K8] Gal（1-16）-NH2和c [D4，K8] Gal（1-12）-NH2中Gly1残基的去除导致螺旋构象的丧失和结合力的降低在GalR1受体处而不是在GalR2受体处。 Gly1缺陷类似物获得的核Overhauser增强确实显示了在N末端序列中存在新生的螺旋结构。通过用鸟氨酸残基取代Lys8或通过将单个赖氨酸残基的位置从8个更改为7个来减小c [D4，K8] Gal（1-16）-NH2的环结构尺寸，同时伴有螺旋结构的完全丧失并大大降低受体亲和力从获得的一系列环状甘丙肽（1-16）-NH2类似物的数据得出的结论是，环结构尺寸和N末端甘氨酸残基的存在对于稳定这些化合物中的N末端螺旋都很重要。但是，尽管N末端螺旋构成了化合物c [D4，K8] Gal（1-16）-NH2和c [D4，K8] Gal（1-12）-NH2构象集合的主要部分，但这些肽但是，能够在解决方案中采用其他构型。因此，环状甘丙肽类似物采用N末端螺旋并结合GalR1受体的能力之间的相关性可以被认为是可行的假设。

著录项

相似文献

  • 外文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号