Silva Elipe M V, Bednarek M A, Gao Y D
Department of Drug Metabolism, Merck Research Laboratories, Rahway, NJ, USA.
Biopolymers. 2001 Dec;59(7):489-501. doi: 10.1002/1097-0282(200112)59:7<489::AID-BIP1054>3.0.CO;2-S.
Human ghrelin, the first recognized natural ligand of growth hormone secretagogue growth hormone secretagogue receptors (GHS-Rs) (M. Kojima, H. Hosada, Y. Date, M. Nakazato, H. Matsuo, and K. Kangawa, Nature, 1999, Vol. 402, pp. 656-660), consists of 28 amino acids of which Ser3 is modified by n-octanoylation. This new peptide hormone has been implicated not only in regulation of the GH secretion but also in regulation of food intake. The discovery of ghrelin opens up more opportunities to study the relationship of ghrelin with metabolic diseases. Until now, only mass spectometry analysis has been reported on the structure of ghrelin. NMR analysis is a suitable way to study if any tertiary structure of unbound ghrelin is present in solution. NMR studies were carried out on human ghrelin and its five truncated analogs. The full-length ghrelin and its fragments exhibited random coil behavior in aqueous solution. Additional studies were carried out on the shortest active segment of human ghrelin, which consists of the first five amino acids of the ghrelin sequence (M. A. Bednarek, S. D. Feighner, S.-S. Pong, K. K. McKee, D. L. Hreniuk, M. V. Silva, V. A. Warrem, A. D. Howard, L. H. Y. Van der Ploeg, and J. V. Heck, Journal of Medical Chemistry, 2000, Vol. 43, pp. 4370-4376), to compare the spectral features with their counterparts in the full-length ghrelin. The NMR data showed behavior similar to ghrelin except for two additional nuclear Overhauser effects (NOEs) between the Phe4 NH and the protons of the beta-methylene of Ser3. CD on human ghrelin and its short active analog in water were indicative of random coil peptides. Molecular modeling based on NMR data was carried out to probe which structural features were similar to growth hormone-releasing peptide-6 (GHRP-6), a hexapeptide that binds to GHS-R releasing GH and stimulating food intake. Modeling suggested some similarities, but they were not of a nature to account for binding properties of these compounds.
人胃饥饿素是生长激素促分泌素受体（GHS-Rs）首个被识别的天然配体（M. 小岛、细田博、伊达洋、中里真、松尾浩和川合健，《自然》，1999年，第402卷，第656 - 660页），由28个氨基酸组成，其中Ser3被正辛酰化修饰。这种新的肽激素不仅与生长激素分泌的调节有关，还与食物摄入的调节有关。胃饥饿素的发现为研究其与代谢疾病的关系开辟了更多机会。到目前为止，关于胃饥饿素的结构仅有质谱分析的报道。核磁共振（NMR）分析是研究溶液中未结合的胃饥饿素是否存在任何三级结构的合适方法。对人胃饥饿素及其五个截短类似物进行了NMR研究。全长胃饥饿素及其片段在水溶液中表现出无规卷曲行为。对人胃饥饿素最短的活性片段进行了进一步研究，该片段由胃饥饿素序列的前五个氨基酸组成（M. A. 贝德纳雷克、S. D. 费格纳、S.-S. 庞、K. K. 麦基、D. L. 赫雷纽克、M. V. 席尔瓦、V. A. 沃勒姆、A. D. 霍华德、L. H. Y. 范德普洛格和J. V. 赫克，《药物化学杂志》，2000年，第43卷，第4370 - 4376页），以将其光谱特征与其在全长胃饥饿素中的对应物进行比较。NMR数据显示其行为与胃饥饿素相似，只是在Phe4 NH与Ser3的β - 亚甲基质子之间有两个额外的核Overhauser效应（NOE）。对人胃饥饿素及其短活性类似物在水中进行的圆二色性（CD）分析表明它们是无规卷曲肽。基于NMR数据进行了分子建模，以探究哪些结构特征与生长激素释放肽 - 6（GHRP - 6）相似，GHRP - 6是一种与GHS - R结合以释放生长激素并刺激食物摄入的六肽。建模表明存在一些相似性，但这些相似性不足以解释这些化合物的结合特性。
