Conformation-function relationships in LHRH analogs. II. Conformations of LHRH peptide agonists and antagonists.

G V Nikiforovich, G R Marshall
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Abstract

Systematic energy calculations were performed for a series of LHRH analogs including five agonists with substitutions of D- or N-Me-amino acid residues in positions 4, 6 and 7, and five antagonists with substitutions of D-, N-Me- or alpha-Me-amino acid residues in positions 1, 2, 3, 6, 7 and 10, as well as a bicyclic LHRH antagonist. The geometrical shapes of the calculated low-energy backbone structures for each compound were compared to those of LHRH itself. It appeared that the beta-II' turn at the Tyr5-Gly6-Leu7-Arg8 central tetrapeptide is the common structure for all LHRH agonists considered. LHRH antagonists also possess a common chain reversal in the central tetrapeptide, but it is different from that for LHRH agonists. The LHRH agonists share a similar low-energy conformer at the level of the entire peptide backbone. A characteristic feature of this conformer is a 'surface' formed by a 'polygon' with hydrophobic moieties of pGlu1, Trp3, Tyr5, Leu7 and Pro9 in the corners and with the side chain of the His2 residue in the middle, the latter being crucial for a manifestation of LHRH agonistic activity. Since the N-terminal tripeptide of LHRH presumably participates in a direct interaction with specific receptors, it is legitimate to suggest that the beta-II' turn in the central tetrapeptide maintains the proper spatial arrangement of the N-terminal tripeptide. On the other hand, LHRH antagonists considered in this study were shown to possess low-energy structures, with the spatial arrangement of the residues in the N-terminal tripeptide similar to that of agonists. This would suggest a new approach to the design of LHRH antagonists, namely by stabilizing this specific arrangement, rather than the beta-II' turn in the central tetrapeptide.

LHRH类似物的构象-函数关系。2LHRH肽激动剂和拮抗剂的构象。
我们对一系列LHRH类似物进行了系统的能量计算,包括5种在4、6和7位取代D-或N-Me氨基酸残基的激动剂,5种在1、2、3、6、7和10位取代D-、N-Me或α - me氨基酸残基的拮抗剂,以及1种双环LHRH拮抗剂。计算出的每个化合物的低能主链结构的几何形状与LHRH本身的几何形状进行了比较。在Tyr5-Gly6-Leu7-Arg8中心四肽上的β - ii '转似乎是所有LHRH激动剂的共同结构。LHRH拮抗剂在中心四肽中也具有共同的链反转,但与LHRH激动剂不同。LHRH激动剂在整个肽主链的水平上具有相似的低能量构象。该构象的一个特征是“表面”是由一个“多边形”组成的,其角上有pGlu1、Trp3、Tyr5、Leu7和Pro9的疏水部分,中间有His2残基的侧链,后者对于LHRH激动活性的表现至关重要。由于LHRH的n端三肽可能参与了与特定受体的直接相互作用,因此可以合理地认为,中央四肽的β - ii '转向维持了n端三肽的适当空间排列。另一方面,本研究中考虑的LHRH拮抗剂具有低能量结构,其n端三肽残基的空间排列与激动剂相似。这将为LHRH拮抗剂的设计提供一种新的方法,即通过稳定这种特定的排列,而不是中央四肽的β - ii '转位。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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