Insertion of a synthetic switch into insulin provides metabolite-dependent regulation of hormone–receptor activation

Abstract

Ligand-dependent conformational switches are ubiquitous in biological macromolecules, from allosteric proteins to RNA riboswitches. Molecular design of artificial switches provides a general strategy to test relationships between macromolecular structure and function. The present study exploited recent structures of complexes between an ancestral signaling protein (insulin) and the ectodomain of its cellular receptor to insert a metabolite-regulated switch into the hormone. Whereas binding of ligands often stabilizes structure, this design envisioned metabolite-dependent “opening” of a closed, inactive insulin conformation. Assessment of hormone-directed receptor autophosphorylation and a downstream signaling cascade in liver-derived cells demonstrated that binding of metabolite (a monosaccharide) enabled hormonal signaling. These results suggest a mechanism-based strategy to design “smart” glucose-responsive analogs to more safely treat insulin-dependent diabetes mellitus.

Description
item.page.description.tableofcontents
item.page.relation.haspart
Cite As
Chen YS, Gleaton J, Yang Y, et al. Insertion of a synthetic switch into insulin provides metabolite-dependent regulation of hormone-receptor activation. Proc Natl Acad Sci U S A. 2021;118(30):e2103518118. doi:10.1073/pnas.2103518118
ISSN
Publisher
Series/Report
Sponsorship
Major
Extent
Identifier
Relation
Journal
Proceedings of the National Academy of Sciences (PNAS)
Source
PMC
Alternative Title
Type
Article
Number
Volume
Conference Dates
Conference Host
Conference Location
Conference Name
Conference Panel
Conference Secretariat Location
Version
Final published version
This item is under embargo {{howLong}}