通过核磁共振氢谱确定的内皮素B受体选择性拮抗剂RES-701-1的溶液结构

Solution structure of endothelin B receptor selective antagonist RES-701-1 determined by 1H NMR spectroscopy.

作者信息

Katahira R, Shibata K, Yamasaki M, Matsuda Y, Yoshida M

机构信息

Tokyo Research Laboratories, Kyowa Hakko Kogyo Co. Ltd., Japan.

出版信息

Bioorg Med Chem. 1995 Sep;3(9):1273-80. doi: 10.1016/0968-0896(95)00122-w.

DOI:10.1016/0968-0896(95)00122-w

PMID:8564420

Abstract

The three-dimensional structure of the endothelin B receptor (ETB) selective antagonist RES-701-1 has been determined by 1H NMR in deuterated dimethyl sulphoxide. RES-701-1 consists of 16 amino acid residues with a novel internal linkage between the beta-carboxyl group of Asp9 and the alpha-amino group of Gly1. The structural calculations were carried out with the combined use of distance geometry and simulated annealing. The result indicates that RES-701-1 adopts an extraordinary folding; the 'tail' (Trp10-Trp16) passes through the 'ring' region (Gly1-Asp9). Several critical NOEs directly support this extraordinary folding. The folding of RES-701-1 turned out to be the same as that Frèchet et al. calculated for RP 71955 which possesses the same internal linkage as RES-701-1. The obtained structure suggested that the region consisting of Thr6, Ala7, Tyr14 and Tyr15 and/or, the region consisting of Asn2, Tyr14 and Tyr15 are involved in a binding with ETB.

摘要

内皮素B受体（ETB）选择性拮抗剂RES - 701 - 1的三维结构已通过在氘代二甲基亚砜中的1H NMR确定。RES - 701 - 1由16个氨基酸残基组成，在Asp9的β - 羧基与Gly1的α - 氨基之间存在一种新型的内部连接。结构计算通过距离几何和模拟退火相结合的方法进行。结果表明RES - 701 - 1呈现出一种非同寻常的折叠方式；“尾巴”（Trp10 - Trp16）穿过“环”区域（Gly1 - Asp9）。几个关键的核Overhauser效应（NOE）直接支持了这种非同寻常的折叠。RES - 701 - 1的折叠结果与弗雷谢等人针对具有与RES - 701 - 1相同内部连接的RP 71955计算的结果相同。所获得的结构表明，由Thr6、Ala7、Tyr14和Tyr15组成的区域和/或由Asn2、Tyr14和Tyr15组成的区域参与了与ETB的结合。