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Structure-based survey of ligand binding in the human insulin receptor
  • Judith Klein-Seetharaman,
  • Whitney Vizgaudis,
  • Lokender Kumar
Judith Klein-Seetharaman
Colorado School of Mines
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Whitney Vizgaudis
Colorado School of Mines
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Lokender Kumar
Colorado School of Mines
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Abstract

The insulin receptor is a membrane protein responsible for regulation of nutrient balance and therefore 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 tyrosine kinase 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.

Peer review status:UNDER REVIEW

17 May 2021Submitted to British Journal of Pharmacology
19 May 2021Assigned to Editor
19 May 2021Submission Checks Completed
31 May 2021Reviewer(s) Assigned