Liu X, Stewart J M, Gera L, Kotovych G
Department of Chemistry, University of Alberta, Edmonton, Canada.
Biopolymers. 1993 Aug;33(8):1237-47. doi: 10.1002/bip.360330810.
Bradykinin (BK) is a peptide hormone with sequence Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9 and has been implicated in a multitude of pathophysiological processes such as the ability to lower systemic blood pressure and stimulate pain. BK analogues having bulky, beta-branched D-aliphatic residues at position 7 combined with bulky L-aliphatic residues at position 8 have now been observed to be strong antagonists. Conformational studies based on two-dimensional nmr experiments in methanol/water (80/20 v/v) were carried out on several such active antagonists in a polar solvent. Included in this study were the very active antagonists, [D-Arg0,Hyp3,Thi5,D-Cpg7,Cpg8]-BK [Cpg: alpha-cyclo-pentyl-glycine; Hyp: trans-4-hydroxy-L-proline; Thi: beta-(2-thienyl)-L-alanine] (I), [D-Arg0,Hyp3,D-Cpg7,Cpg8]-BK (II), as well as its variant with D-Cpg7 replaced by Cpg7, namely [D-Arg0,Hyp3,Cpg7,Cpg8]-BK (III). A turn-like structure, which coexists with the extended conformation, was observed between residues 2 and 5 for the most active antagonists I and II, in direct correlation with the peptide activities. No turn-like structure was found for residues 6-9. In peptide III, a turn-like structure was not identified. The existence of a turn at the C-terminal end of bradykinin and its analogues has been predicted by empirical calculations and supported by nmr measurements. But the present nmr study on the most active antagonists (I, II) does not support this hypothesis. Instead, the data suggest that a turn-like structure between residues 2 and 5 could be important for antagonist activity. Finally, one weak inhibitor [D-Cpg7]-BK (IV) showed no defined secondary structure.
缓激肽（BK）是一种肽类激素，其序列为Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9，并且与多种病理生理过程有关，如降低全身血压和刺激疼痛的能力。现已观察到，在第7位具有庞大的β-支链D-脂肪族残基并在第8位结合庞大的L-脂肪族残基的BK类似物是强效拮抗剂。在极性溶剂中，对几种此类活性拮抗剂进行了基于甲醇/水（80/20 v/v）二维核磁共振实验的构象研究。该研究包括活性很强的拮抗剂[D-Arg0,Hyp3,Thi5,D-Cpg7,Cpg8]-BK [Cpg：α-环戊基甘氨酸；Hyp：反式-4-羟基-L-脯氨酸；Thi：β-(2-噻吩基)-L-丙氨酸]（I）、[D-Arg0,Hyp3,D-Cpg7,Cpg8]-BK（II），以及其D-Cpg7被Cpg7取代的变体，即[D-Arg0,Hyp3,Cpg7,Cpg8]-BK（III）。对于活性最强的拮抗剂I和II，在残基2和5之间观察到一种与伸展构象共存的类似转角的结构，这与肽的活性直接相关。在残基6 - 9未发现类似转角的结构。在肽III中，未鉴定出类似转角的结构。缓激肽及其类似物C末端存在转角已通过经验计算预测，并得到核磁共振测量的支持。但目前对活性最强的拮抗剂（I、II）的核磁共振研究不支持这一假设。相反，数据表明残基2和5之间的类似转角结构可能对拮抗剂活性很重要。最后，一种弱抑制剂[D-Cpg7]-BK（IV）未显示出明确的二级结构。
