Grace Christy Rani R, Erchegyi Judit, Reubi Jean Claude, Rivier Jean E, Riek Roland
Structural Biology Laboratory, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Biopolymers. 2008 Dec;89(12):1077-87. doi: 10.1002/bip.21060.
The three-dimensional NMR structures of seven octapeptide analogs of somatostatin (SRIF), based on octreotide, with the basic sequence H-Cpa/Phe2-c[DCys3-Xxx7-DTrp/DAph(Cbm)8-Lys9-Thr10-Cys14]-Yyy-NH2 (the numbering refers to the position in native SRIF), with Xxx7 being Aph(Cbm)/Tyr/Agl(NMe,benzoyl) and Yyy being Nal/DTyr/Thr, are presented here. Most of these analogs exhibit potent and highly selective binding to sst2 receptors, and all of the analogs are antagonists inhibiting receptor signaling. Based on their consensus 3D structure, the pharmacophore of the sst2-selective antagonist has been defined. The pharmacophore involves the side chains of Cpa2, DTrp/DAph(Cbm)8, and Lys9, with the backbone for most of the sst2-selective antagonists comprised a Type-II' beta-turn. Hence, the sst2-selective antagonist pharmacophore is very similar to the sst2-selective agonist pharmacophore previously described.
本文展示了基于奥曲肽的七种生长抑素(SRIF)八肽类似物的三维核磁共振结构,其基本序列为H-Cpa/Phe2-c[DCys3-Xxx7-DTrp/DAph(Cbm)8-Lys9-Thr10-Cys14]-Yyy-NH2(编号指天然SRIF中的位置),其中Xxx7为Aph(Cbm)/Tyr/Agl(NMe,苯甲酰基),Yyy为Nal/DTyr/Thr。这些类似物大多对sst2受体表现出强效且高度选择性的结合,并且所有类似物均为抑制受体信号传导的拮抗剂。基于它们的共有三维结构,已确定了sst2选择性拮抗剂的药效基团。该药效基团涉及Cpa2、DTrp/DAph(Cbm)8和Lys9的侧链,大多数sst2选择性拮抗剂的主链包含一个II'型β-转角。因此,sst2选择性拮抗剂的药效基团与先前描述的sst2选择性激动剂的药效基团非常相似。