Structure‐based survey of ligand binding in the human insulin receptor

Abstract

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

Targeting the cell's gatekeepers for novel drug discovery

“…In particular, their review underscores the power of structural snapshots in facilitating the visualization of ligand‐receptor interaction and how this information can be utilized to drive rational ligand discovery with an emphasis on drug selectivity and efficacy. Klein‐Seetharaman and co‐author summarize recent advances on the insulin receptor, which is critically involved in the physiology of nutrient balance and represents an important therapeutic target in diabetes mellitus and metabolic disorders (Kumar & Klein‐Seetharaman, 2022). In particular, these authors present a comprehensive analysis of the emerging structural data to draw mechanistic insights into ligand binding, activation and pharmacology of the insulin receptor, and also discuss how these insights may facilitate the design of potential therapeutics targeting this receptor.…”

NPC43 Activates Insulin Receptor in White Adipose Tissue and Stimulates Adipocyte Glucose Uptake to Mitigate Hyperglycemia in Type 1 And 2 Diabetic Mice

“…NPC43 also cooperates with insulin to stimulate skeletal muscle glucose uptake and attenuates hepatic G6pc-driven gluconeogenesis [25]. Furthermore, NPC43 can directly interact with Insrα [25,27] and activates native liver Insr protein in a cell-free, in vitro phosphorylation system [25]. Thus, liver and gastrocnemius are two identified target organs of NPC43 in which NPC43 can restore or activate Insr signaling to counter hyperglycemia in T1D and T2D mice [25,26].…”

Modulation of the antagonistic properties of an insulin mimetic peptide by disulfide bridge modifications

“… 10 The storage and distribution of pharmaceutical preparations of insulin in solution are also not without problems due to the tendency of insulin to aggregate at higher temperatures or in response to shaking in the form of inactive fibrils. 11 These facts logically initiated efforts to design artificial molecules 12 , 13 , 14 , 15 that would mimic the action of insulin on IR and could lead to the development of active, metabolically more stable, or even orally available IR agonists. On the other hand, substances capable of inhibiting, either partially or completely, the activation of the receptor by insulin could find application in the control of hypoglycemic states in patients caused by insulin doses that are too high 16 , 17 or in preventing problems associated with hyperinsulinemia.…”