Senn H, Klaus W
Department of Pharmaceutical Research-New Technologies F. Hoffmann-LaRoche Ltd, Basel, Switzerland.
J Mol Biol. 1993 Aug 5;232(3):907-25. doi: 10.1006/jmbi.1993.1439.
The snake venom protein flavoridin, a polypeptide of 70 amino acid residues, is a potent inhibitor of blood platelet aggregation. It binds to cell-surface integrin receptors such as the fibrinogen receptor glycoprotein IIb/IIIa. The inhibitory properties of flavoridin have been attributed to the tripeptide segment Arg-Gly-Asp (residues 49 to 51). This paper describes the determination of the three-dimensional structure of flavoridin in aqueous solution based on two-dimensional nuclear magnetic resonance spectroscopy. A family of 18 conformers was selected to characterize the solution structure. The molecule comprises two structural domains, an N-terminal unit extending from residues 1 to 25, and a C-terminal unit from residues 26 to 70. Whereas the mutual spatial orientation of these regions is not well defined, each one is well organized within itself. The segment 26 to 70, which is homologous to the sequence of the snake toxins echistatin and eristostatin, shows an average value of 1.0 A for the root-mean-square deviations of the backbone atoms among the 18 conformers. The structure of flavoridin consists essentially of non-repetitive elements such as tight turns and loops, whose location and conformation are characterized in this paper. With the exception of two short regions of antiparallel beta-sheet, no classic element of protein secondary structure is present. The six disulphide bridges, which have been mapped by applying a novel computational strategy (see accompanying paper), are the dominant organizational feature of the polypeptide fold of flavoridin. Two of the bridges are located in the N-terminal domain, three in the C-terminal domain and one connects the two structural units. The mobile RGD recognition sequence for integrins is located peripheral to the core region of the C-terminal domain at the most exposed end of a nine residue loop structure, which is attached to a short beta-sheet. The C terminus is close to this loop structure.
蛇毒蛋白flavoridin是一种由70个氨基酸残基组成的多肽，是血小板聚集的强效抑制剂。它与细胞表面整合素受体如纤维蛋白原受体糖蛋白IIb/IIIa结合。flavoridin的抑制特性归因于三肽片段Arg-Gly-Asp（第49至51位残基）。本文描述了基于二维核磁共振光谱法测定水溶液中flavoridin的三维结构。选择了18个构象体家族来表征溶液结构。该分子由两个结构域组成，一个N端单元从第1位残基延伸至第25位残基，一个C端单元从第26位残基延伸至第70位残基。虽然这些区域的相互空间取向不太明确，但每个区域自身都组织良好。与蛇毒素echistatin和eristostatin序列同源的第26至70位片段，在18个构象体中主链原子的均方根偏差平均值为1.0埃。flavoridin的结构主要由非重复元件如紧密转角和环组成，本文对其位置和构象进行了表征。除了两个短的反平行β-折叠区域外，不存在蛋白质二级结构的经典元件。通过应用一种新颖的计算策略（见随附论文）绘制的六个二硫键是flavoridin多肽折叠的主要组织特征。其中两个桥位于N端结构域，三个位于C端结构域，一个连接两个结构单元。整合素的可移动RGD识别序列位于C端结构域核心区域的外围，在一个与短β-折叠相连的九个残基环结构的最暴露端。C端靠近这个环结构。
