Nuclear magnetic resonance analysis and conformational characterization of a cyclic decapeptide antagonist of gonadotropin-releasing hormone.
Nuclear magnetic resonance analysis and conformational characterization of a cyclic decapeptide antagonist of gonadotropin-releasing hormone.
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促性腺激素释放激素环状十肽拮抗剂的核磁共振分析和构象表征。
DOI：
10.1021/bi00383a036
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发表时间：
1987
期刊：
影响因子：
2.9
通讯作者：
Gierasch,LM
中科院分区：
文献类型：
--
作者：
Baniak2nd,EL;Rivier,JE;Struthers,RS;Hagler,AT;Gierasch,LM
摘要：对促性腺激素释放激素环十肽拮抗剂cyc/o-(A3*- prol -d - pclphe2 -d - trp3 - ser4 - tyr5 -d - trp6 - nmeleu7 - arg8 - pro9 -/3-Alal0)进行了500 MHz二维质子核磁共振波谱分析。拮抗剂存在于两种缓慢相互转换的构象中。所有数据都与一种形式具有全反式肽键和另一种形式具有顺式/3- alaloo - a3 - prol键的结论一致。采用顺序配位方法，除丝氨酸和酪氨酸羟基以及精氨酸的C7、C5和胍基质子外，两种构象异构体的主链和侧链质子均得到了化学位移配位。光谱参数的温度依赖性和观察到的核Overhauser效应的大小支持了拮抗剂的两个构象由两个/3旋（IT型，D-Trp6-NMeLeu7； II型，A3-Prol-D-pClPhe2）组成的解释，这些构象由延伸的反平行/3状链连接。促睾酮释放激素，pgll - his2 - trp3 - ser4 - tyr5 - gly6 - leu7 - arg8 - pro9 - glyl0 - nh2，是一种线性十肽激素，由下丘脑分泌，作用于垂体，刺激促黄体生成素和促卵泡激素的释放。这些激素反过来又在性腺中作为排卵或精子发生的调节剂（Vander等，1970；Matsuo等，1971；Burgus等，1972）。因此，GnRH1已成为潜在生殖治疗或避孕药物类似物设计的目标（Vickery et al., 1984; Karten & Rivier, 1986）。虽然许多类似物作为拮抗剂或超级激动剂具有高度活性，但在大多数情况下，它们的设计并非基于构象原则。相对而言，人们对激素及其类似物结合受体的结构要求知之甚少。像许多肽激素一样，GnRH是一种高度柔韧性的分子，存在于溶液中，是几种构象的平衡混合物（Sprecher & Momany, 1979; Kopple, 1981a, b, 1983）。尽管如此，其首选构象的工作模型可能与受体结合构象一致。大多数GnRH模型的一个共同特征是Gly6-Leu7的1 /3转，最初由Momany根据经验构象能计算提出（Momany, 1976a, b）。支持GnRH在生物活性构象中存在这种转变的证据来自于Gly6的d -氨基酸替代类似物的活性（Chandrasekaren等人，1973；Monahan等人，1973），Leu7的a -甲基亮氨酸类似物的活性（Ling & Vale, 1975; Tonelli, 1976），以及使Gly6和Leu7的f角达到a/3-turn特征值的内酰胺桥接类似物（Freidinger等人，1980）。最近，已经合成了通过环化约束构象的活性GnRH类似物。o 'c /o-(Tyr-D-Trp-Leu-Arg-Trp-Pro)，而
Revised Manuscript Received December 2, 1986 abstract: Two-dimensional proton nuclear magnetic resonance spectroscopy at 500 MHz has been carried out on the cyclic decapeptide antagonist of gonadotropin-releasing hormone: cyc/o-(A3*-Prol-D-pClPhe2-D-Trp3-Ser4-Tyr5-D-Trp6-NMeLeu7-Arg8-Pro9-/3-Alal0). The antagonist exists in two slowlyinterconverting conformations. All data are consistent with the conclusion that one form has all-trans peptide bonds and the other has a cis/3-AlalO-A3-Prol bond. With the use of sequential assignment methods, chemical shift assignments were obtained for all backbone and side-chain protons of both conformational isomers except for the serine and tyrosine hydroxyl groups and the C7, C5, and guanidinium group protons of the arginine. Temperature dependence of spectral parameters and magnitudes of observed nuclear Overhauser effects support the interpretation that both conformers of the antagonist consist of two/3-turns (type IT, D-Trp6-NMeLeu7; type II, A3-Prol-D-pClPhe2) connectedby extended antiparallel/3-like strands.Clonadotropin-releasing hormone, pGlul-His2-Trp3-Ser4-Tyr5-Gly6-Leu7-Arg8-Pro9-Glyl0-NH2, is a linear decapeptide hormone that is secreted by the hypothalamus and acts on the pituitary gland where it stimulates therelease of luteinizing hormone and follicle-stimulating hormone. These hormones in turn act at the gonads as regulators of ovulation or spermatogenesis (Vander et al., 1970; Matsuo et al., 1971; Burgus et al., 1972). Hence, GnRH1 has been a target of analogue design for potential reproductive therapy or con-traceptive agents (Vickery et al., 1984; Karten & Rivier, 1986). While many of these analogues are highly active either as antagonists or superagonists, in most cases their design has not been based on conformational principles. Relatively little is known of the structural requirements of the hormone and its analogues for receptor binding. Like many peptide hormones, GnRH is a highly flexible molecule that exists in solution as an equilibrium mixture of several conformers (Sprecher & Momany, 1979; Kopple, 1981a, b, 1983). Nonetheless, working models for its preferred conformation that may coincide with its receptor-bound con-formation have emerged. A feature common to most models of GnRH is a/3-turn at Gly6-Leu7, originally suggested by Momany from empirical conformational energy calculations (Momany, 1976a, b). Supportfor the presence of this turn in the bioactive conformation of GnRH comes from the activities of analogues with D-amino acid substitutions for Gly6 (Chandrasekaren et al., 1973; Monahan et al., 1973), an analogue with an A-methylleucine for Leu7 (Ling & Vale, 1975; Tonelli, 1976), and a lactam-bridged analogue that forces the f angle of Gly6 and the f angle of Leu7 to values characteristic of a/3-turn (Freidinger et al., 1980). Recently, active analogues of GnRH that are conformationally constrained via cyclization have been synthesized. A cyclic hexapeptide, o’c/o-(Tyr-D-Trp-Leu-Arg-Trp-Pro), while
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下丘脑黄体生成激素释放因子的合成类似物，具有增强的激动剂或拮抗剂特性。
影响因子：
2.9
作者：
M. Monahan;M. Amoss;H. A. Anderson;W. Vale
通讯作者：
W. Vale
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DOI：
10.1016/0006-291x(77)91310-9
发表时间：
1977
影响因子：
3.1
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
10.1016/s0006-291x(77)80186-1
发表时间：
1977
影响因子：
3.1
作者：
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通讯作者：
H. Scheraga