Novel sst4-selective somatostatin (SRIF) agonists.: 4.: Three-dimensional consensus structure by NMR
Novel sst4-selective somatostatin (SRIF) agonists.: 4.: Three-dimensional consensus structure by NMR
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DOI：
10.1021/jm030246p
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发表时间：
2003-12-18
影响因子：
7.3
通讯作者：
Riek, R
中科院分区：
文献类型：
--
作者：
Grace, CRR;Koerber, SC;Riek, R
本文报道了八个生长抑素环八肽类似物（SRIF）的三维NMR结构。这些类似物具有基本序列H-c[Cys（3）-Phe（6）-Xxx（7）-yyy（8）-Lys（9）-Thr（10）-Zzz（11）-Cys（14）]-OH（编号是指天然SRIF中的位置），其中Xxx（7）是Phe/Ala/Tyr，Yyy（8）是Trp/DTrp/D-苏型-β-Me 2Nal/L-苏型-β-Me 2Nal，且Zzz（11）是Phe/Ala，表现出与人SRIF 4型（sst（4））受体的有效和高选择性结合。构象表明，这些类似物的主链不具有通常文献中报道的sst（2）亚型选择性类似物的II型β-转角。相反，这些结构含有Yyy（8）、Lys（9）和Phe（6）或Phe（11）的侧链的独特排列。这些类似物的构象偏好和生物学分析结果（本系列的第1-3部分，Rivier等人，Erchegyi等人，和Erchegyi等人，J.Med.Chem.2003，本期的前几篇论文）允许详细研究SRIF的结构-活性关系。sst（4）-选择性类似物的结合口袋处的建议共识结构基序需要吲哚/2-萘基环，赖氨酸侧链和另一个芳环之间的一组独特的距离。这个基序是必要的，足以解释所有研究的类似物的结合亲和力，是从sst（2）/sst（5）的选择性建议的现有模型不同。
The three-dimensional NMR structures of eight cyclic octapeptide analogues of somatostatin (SRIF) are described. These analogues, with the basic sequence H-c[Cys(3)-Phe(6)-Xxx(7)-yyy(8)-Lys(9)-Thr(10)-Zzz(11)-Cys(14)]-OH (the numbering refers to the position in native SRIF), with Xxx(7) being Phe/Ala/Tyr, Yyy(8) being Trp/DTrp/D-threo-beta-Me2Nal/L-threo-beta-Me2Nal, and Zzz(11) being Phe/Ala, exhibit potent and highly selective binding to human SRIF type 4 (sst(4)) receptors. The conformations reveal that the backbones of these analogues do not have the usual type-II' beta-turn reported in the literature for sst(2)-subtype-selective analogues. Instead, the structures contain a unique arrangement of side chains of Yyy(8), Lys(9), and Phe(6) or Phe(11). The conformational preferences and results from biological analyses of these analogues (parts 1-3 of this series, Rivier et al., Erchegyi et al., and Erchegyi et al., J. Med. Chem. 2003, preceding papers in this issue) allow a detailed study of the structure-activity relationship of SRIF. The proposed consensus structural motif at the binding pocket for the sst(4)-selective analogues requires a unique set of distances between an indole/2-naphthyl ring, a lysine side chain, and another aromatic ring. This motif is necessary and sufficient to explain the binding affinities of all of the analogues studied and is distinct from the existing model suggested for sst(2)/sst(5) selectivity.