Nonspanning bivalent ligands as improved surface receptor binding inhibitors of the cholera toxin B pentamer
Nonspanning bivalent ligands as improved surface receptor binding inhibitors of the cholera toxin B pentamer
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DOI：
10.1016/j.chembiol.2004.06.008
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发表时间：
2004-09-01
影响因子：
--
通讯作者：
Fan, EK
中科院分区：
文献类型：
--
作者：
Pickens, JC;Mitchell, DD;Fan, EK
合成了一系列不同长度的双价配体，用于抑制霍乱毒素与受体的结合过程。竞争性表面受体结合测定显示，相对于组成单价配体的显著效力增益独立于延伸的二价配体跨越毒素五聚体内的结合位点的能力而实现。考虑到与毒素五聚体复合的每种配体的晶体学分析，检查了可以解释IC 50值的意外改善的几种模型。证据表明，在受体结合表面的空间位阻可能发挥作用。我们的研究结果表明，使用相对较短的，“非跨越”的二价配体，或类似的拓扑结构和散装的单价配体可能是一种有效的方式，阻止多聚体蛋白与其细胞表面受体的相互作用。
A series of bivalent ligands of varying length were synthesized to inhibit the receptor-binding process of cholera toxin. Competitive surface receptor binding assays showed that significant potency gains relative to the constituent monovalent ligands were achieved independently from the ability of the extended bivalent ligands to span binding sites within the toxin pentamer. Several models that could account for the unexpected improvement in IC50 values are examined, taking into account crystallographic analysis of each ligand in complex with the toxin pentamer. Evidence is presented that steric blocking at the receptor binding surface may play a role. The results of our study suggest that the use of relatively short, "nonspanning" bivalent ligands, or monovalent ligands of similar topology and bulk may be an effective way of blocking the interaction of multimeric proteins with their cell surface receptors.