Grace Christy Rani R, Erchegyi Judit, Koerber Steven C, Reubi Jean Claude, Rivier Jean, Riek Roland
Structural Biology Laboratory, The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, California 92037, USA.
J Med Chem. 2006 Jul 27;49(15):4487-96. doi: 10.1021/jm060363v.
The 3D NMR structures of six octapeptide agonist analogues of somatostatin (SRIF) in the free form are described. These analogues, with the basic sequence H-DPhe/Phe2-c[Cys3-Xxx7-DTrp8-Lys9-Thr10-Cys14]-Thr-NH2 (the numbering refers to the position in native SRIF), with Xxx7 being Ala/Aph, exhibit potent and highly selective binding to human SRIF type 2 (sst2) receptors. The backbone of these sst2-selective analogues have the usual type-II' beta-turn reported in the literature for sst2/3/5-subtype-selective analogues. Correlating the biological results and NMR studies led to the identification of the side chains of DPhe2, DTrp8, and Lys9 as the necessary components of the sst2 pharmacophore. This is the first study to show that the aromatic ring at position 7 (Phe7) is not critical for sst2 binding and that it plays an important role in sst3 and sst5 binding. This pharmacophore is, therefore, different from that proposed by others for sst2/3/5 analogues.
本文描述了六种游离形式的生长抑素(SRIF)八肽激动剂类似物的三维核磁共振结构。这些类似物的基本序列为H-DPhe/Phe2-c[Cys3-Xxx7-DTrp8-Lys9-Thr10-Cys14]-Thr-NH2(编号指天然SRIF中的位置),其中Xxx7为Ala/Aph,它们对人SRIF 2型(sst2)受体表现出强效且高度选择性的结合。这些sst2选择性类似物的主链具有文献中报道的sst2/3/5亚型选择性类似物常见的II'型β-转角。将生物学结果与核磁共振研究相关联,确定了DPhe2、DTrp8和Lys9的侧链是sst2药效团的必要组成部分。这是第一项表明7位(Phe7)的芳香环对sst2结合并非关键,且在sst3和sst5结合中起重要作用的研究。因此,这种药效团与其他人提出的sst2/3/5类似物的药效团不同。