Insulin structure and function

Abstract

Throughout much of the last century insulin served a central role in the advancement of peptide chemistry, pharmacology, cell signaling and structural biology. These discoveries have provided a steadily improved quantity and quality of life for those afflicted with diabetes. The collective work serves as a foundation for the development of insulin analogs and mimetics capable of providing more tailored therapy. Advancements in patient care have been paced by breakthroughs in core technologies, such as semisynthesis, high performance chromatography, rDNA-biosynthesis and formulation sciences. How the structural and conformational dynamics of this endocrine hormone elicit its biological response remains a vigorous area of study. Numerous insulin analogs have served to coordinate structural biology and biochemical signaling to provide a first level understanding of insulin action. The introduction of broad chemical diversity to the study of insulin has been limited by the inefficiency in total chemical synthesis, and the inherent limitations in rDNA-biosynthesis and semisynthetic approaches. The goals of continued investigation remain the delivery of insulin therapy where glycemic control is more precise and hypoglycemic liability is minimized. Additional objectives for medicinal chemists are the identification of superagonists and insulins more suitable for non-injectable delivery. The historical advancements in the synthesis of insulin analogs by multiple methods is reviewed with the specific structural elements of critical importance being highlighted. The functional refinement of this hormone as directed to improved patient care with insulin analogs of more precise pharmacology is reported.

Protective hinge in insulin opens to enable its receptor engagement

“…Leu A3 , predicted to clash with αCT, exhibits a residual receptor-binding affinity (0.1% relative to WT insulin) similar to that of ΔPhe B25 . The μIR structure further accounts for effects of C-terminal truncation or modification of the B chain ¶ (41). Truncation at B25 (with Cterminal amide), B26, or B27 yields analogs with complete activity, in accordance with our observations that, beyond Phe B24 , successive C-terminal residues exhibit progressively more limited (B25-B27) or absent (B28-B30) interactions with the μIR.…”

“…Truncation at B25 (with Cterminal amide), B26, or B27 yields analogs with complete activity, in accordance with our observations that, beyond Phe B24 , successive C-terminal residues exhibit progressively more limited (B25-B27) or absent (B28-B30) interactions with the μIR. Modification of the latter residues can modulate pharmacokinetic properties without loss of activity as exploited in clinical formulations (41).…”

Non-equivalent Role of Inter- and Intramolecular Hydrogen Bonds in the Insulin Dimer Interface

“…However, despite decades of intensive research, many questions about the structure of insulin and its mechanism of action remain. The solid state-based structural insight into the insulin molecule is limited to inactive dimeric or hexameric storage forms (1)(2)(3), whereas the insulin monomer represents the active form of the hormone when binding to the insulin receptor (IR). 3 It is also widely accepted that insulin undergoes a profound structural change during this process (4 -6), a hypothesis supported by a plethora of highly dynamic hormone conformers identified by NMR studies (7)(8)(9)(10)(11)(12)(13).…”

“…Attempts to determine the structure of the insulin-IR complex have been unsuccessful so far. However, the regions of the insulin molecule responsible for the interaction with the IR (3,14) or for its dimerization and hexamerization (15,16) have been functionally and structurally identified in a number of insulin analogues.…”

Rational Design of a Novel AMPA Receptor Modulator through a Hybridization Approach

“…2,3 Four distinct genes (GluA1 to 4) encode subunits of the AMPA receptor, each consisting of four discernible domains: an N-terminal region, an extracellular glutamate binding site (ligand binding domain, LBD), a transmembrane region, and a C-terminal domain. 4 Considerable advances have been made in solving the three-dimensional structure of the AMPA receptor. X-ray structures have been reported of protein complexes representing the LBD 5 and more latterly the fulllength receptor.…”