Harnessing Structural Data of Insulin and Insulin Receptor for Therapeutic Designs

Abstract

To lower blood glucose concentration, insulin binds to insulin receptor (IR) that possesses two distinct insulin binding sites to trigger downstream signaling events leading to an increased uptake of glucose into muscle and fat cells. Comprehensive understandings of structural and dynamic mechanisms of insulin and its receptor are essential to design therapeutic agents for treating and delaying the onset of diabetes that affects over 347 million people worldwide. No full-length IR structure is available hitherto. Harnessing the currently available and state-of-the-art sequence and structural data, we have reviewed the insulin, IR, its extracellular domains and transmembrane domain, to derive structure-based clues to regulate aberrant insulin and its receptor. To propose testable hypotheses and future experiments, we have performed literature review, text mining, multiple structural clustering and normal mode analysis on insulin and its receptor. It appears that insulin-receptor interaction involves allostery and conformational changes (including rotation and tilting) to overcome steric clashes. To target a particular aberrant isoform of IRs, we need to identify the subtle yet distinct differences between IR isoforms. To improve the life quality of diabetics, better structure-based designs of insulin mimetics, formulation and nanotechnology-based delivery are required; efforts to bring them to patients necessitate thorough structural understandings of insulin and its receptor.

A Comprehensive Survey of the Roles of Highly Disordered Proteins in Type 2 Diabetes

“…Despite the crucial importance of IR for understanding the molecular mechanisms of physiological and pathological actions of insulin and other ligands of the insulin family, and despite significant efforts of the scientific community, there is no structural information for the whole IR molecule due to the high flexibility of the intact IR, its membrane-bound nature, and its heavily glycosylated status [ 218 ]. However, structural information is available for several fragments of human IR, such as the N-terminal L1-CR-L2 region of ectodomain (residues 28–512, PDB ID: 2HR7) [ 219 ], the entire ectodomain (residues 28–955, PDB ID: 4ZXB, see Figure 18 A) [ 204 ], the transmembrane domain in detergent micelles (residues 913–961, PDB ID: 2MRF, see Figure 18 B) [ 220 ], and the protein kinase domain together and with the preceding juxtamembrane region in a phosphorylated state (residues 956–1283, PDB ID: 4XLV, see Figure 18 C) [ 221 ].…”

Therapeutic Methods Against Insulin Resistance

“…Thereby, the circulating glucose concentration is not directly affected by serum resistin in type 2 DM [93]. The resistin is secreted by macrophages, immune cells, mononuclear leukocytes and bone marrow cells [94][95][96] and it interferes with the activation of IRS-1 [77,95] and/or adenylyl cyclase-associated protein-1 (CAP-1) [91,96]. Therefore, resistin causes insulin resistance by dysfunction in the insulin receptor, endothelial cells and smooth muscle.…”

“…In other words, the D-glucose does not enter in the cell, after the insulin receptor has been attached. A variety of disorders, acquired and/or genetic, can be associated with the development of insulin resistance and are frequently the result of defects in the structure and function of the receptor [46,94,99,110], originating from hyperglycemia and hyperinsulinemia.…”

“…Other hormonal antagonists such as cortisol, growth hormone, glucagon and catecholamines are each capable of producing states of insulin resistance. Therefore, anti-inflammatory drugs [64,65] can reverse or improve this dysfunction of receptor caused by the lipotoxicity of the adipokines [5,69,94,104], as shown in Figure 3. Then, the chronic lipotoxicity of the adipokines in the insulin receptors of obese adults can cause the formation of free radicals, oxidate stress, degeneration and cell death in many cells of the body [4][5][6]108].…”

Structural analysis of protein tyrosine phosphatase 1B reveals potentially druggable allosteric binding sites

“…These multiple conformations may arise because their resolution was carried out under distinct conditions (eg, pH, temperature, the presence of mutations, etc) and by different laboratories. As shown for proteins such as IR and Ras, the multiple structures can be a great source to extract clues regarding the structural dynamics of the proteins of interest, and possibly their functions and regulations. Thus, it is important to develop methods to appropriately choose subsets of structures of the same protein for subsequent studies such as molecular dynamics simulations, mapping of binding sites, molecular docking studies and screening of small molecule binders, and so forth.…”