Cairo Christopher W, Gestwicki Jason E, Kanai Motomu, Kiessling Laura L
Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
J Am Chem Soc. 2002 Feb 27;124(8):1615-9. doi: 10.1021/ja016727k.
Receptor clustering by multivalent ligands can activate signaling pathways. In principle, multivalent ligand features can control clustering and the downstream signals that result, but the influence of ligand structure on these processes is incompletely understood. Using a series of synthetic polymers that vary systematically, we studied the influence of multivalent ligand binding epitope density on the clustering of a model receptor, concanavalin A (Con A). We analyze three aspects of receptor clustering: the stoichiometry of the complex, rate of cluster formation, and receptor proximity. Our experiments reveal that the density of binding sites on a multivalent ligand strongly influences each of these parameters. In general, high binding epitope density results in greater numbers of receptors bound per polymer, faster rates of clustering, and reduced inter-receptor distances. Ligands with low binding epitope density, however, are the most efficient on a binding epitope basis. Our results provide insight into the design of ligands for controlling receptor-receptor interactions and can be used to illuminate mechanisms by which natural multivalent displays function.
多价配体引起的受体聚集能够激活信号通路。原则上,多价配体特征可以控制聚集以及由此产生的下游信号,但配体结构对这些过程的影响尚未完全清楚。我们使用一系列系统变化的合成聚合物,研究了多价配体结合表位密度对模型受体伴刀豆球蛋白A(Con A)聚集的影响。我们分析了受体聚集的三个方面:复合物的化学计量、聚集体形成速率和受体间距。我们的实验表明,多价配体上结合位点的密度强烈影响这些参数中的每一个。一般来说,高结合表位密度导致每个聚合物结合的受体数量更多、聚集速率更快以及受体间距离减小。然而,基于结合表位,低结合表位密度的配体效率最高。我们的结果为控制受体 - 受体相互作用的配体设计提供了见解,并可用于阐明天然多价展示发挥作用的机制。