Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Warsaw, Poland.
Methods Mol Biol. 2023;2627:339-348. doi: 10.1007/978-1-0716-2974-1_19.
The allosteric binding sites are usually located in the flexible areas of proteins, which are hardly visible in the crystal structures. However, there are notable exceptions like allosteric sites in receptors in class B and C of GPCRs, which are located within a well-defined bundle of transmembrane helices. Class B and C evolved from class A and even after swapping of orthosteric and allosteric sites the central binding site persisted and it can be used for easy design of allosteric drugs. However, studying the ligand binding to the allosteric sites in the most populated class A of GPCRs is still a challenge, since they are located mostly in unresolved parts of the receptor's structure, and especially N-terminus. This chapter provides an example of cannabinoid CB1 receptor N-terminal homology modeling, ligand-guided modeling of the allosteric site in GABA receptor, as well as C-linker modeling in the potassium ion channels where the allosteric phospholipid ligand PIP2 is bound.
变构结合位点通常位于蛋白质的柔性区域，这些区域在晶体结构中很难被看到。然而，也有一些显著的例外，如 GPCR 中的 B 类和 C 类受体中的变构结合位点，它们位于一个定义明确的跨膜螺旋束内。B 类和 C 类是从 A 类进化而来的，即使变构结合位点和 orthosteric 结合位点发生了交换，中心结合位点仍然存在，并且可以用于变构药物的设计。然而，研究配体与 GPCR 中最常见的 A 类变构结合位点的结合仍然是一个挑战，因为它们主要位于受体结构中未解决的部分，尤其是 N 端。本章提供了一个示例，说明了大麻素 CB1 受体 N 端同源建模、GABA 受体变构结合位点的配体引导建模，以及钾离子通道中的 C 连接子建模，其中结合了变构磷脂配体 PIP2。
