Department of Physics, Colorado School of Mines, Golden, Colorado, USA.
Department of Chemistry, Colorado School of Mines, Golden, Colorado, USA.
Br J Pharmacol. 2022 Jul;179(14):3512-3528. doi: 10.1111/bph.15777. Epub 2022 Feb 4.
The insulin receptor is a membrane protein responsible for the regulation of nutrient balance; and therefore, it is an attractive target in the treatment of diabetes and metabolic syndrome. Pharmacology of the insulin receptor involves two distinct mechanisms: (1) activation of the receptor by insulin mimetics that bind in the extracellular domain and (2) inhibition of the receptor TK enzymatic activity in the cytoplasmic domain. While a complete structural picture of the full-length receptor comprising the entire sequence covering extracellular, transmembrane, juxtamembrane and cytoplasmic domains is still elusive, recent progress through cryoelectron microscopy has made it possible to describe the initial insulin ligand binding events at atomistic detail. We utilize this opportunity to obtain structural insights into the pharmacology of the insulin receptor. To this end, we conducted a comprehensive docking study of known ligands to the new structures of the receptor. Through this approach, we provide an in-depth, structure-based review of human insulin receptor pharmacology in light of the new structures. LINKED ARTICLES: This article is part of a themed issue on Structure Guided Pharmacology of Membrane Proteins (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.14/issuetoc.
胰岛素受体是一种膜蛋白，负责调节营养平衡；因此，它是治疗糖尿病和代谢综合征的一个有吸引力的靶点。胰岛素受体的药理学涉及两种不同的机制：（1）通过结合在细胞外结构域的胰岛素类似物激活受体，（2）抑制细胞内结构域的受体 TK 酶活性。尽管完整的全长受体的完整结构包括覆盖细胞外、跨膜、近膜和细胞质结构域的整个序列的完整结构仍然难以捉摸，但通过冷冻电子显微镜的最新进展，已经有可能详细描述初始胰岛素配体结合事件。我们利用这个机会获得胰岛素受体药理学的结构见解。为此，我们对新受体结构进行了已知配体的全面对接研究。通过这种方法，我们根据新结构，对人胰岛素受体药理学进行了深入的基于结构的综述。相关文章：本文是膜蛋白结构导向药理学专题的一部分（BJP 75 周年纪念）。要查看本节中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.14/issuetoc.
