Probing the correlation between insulin activity and structural stability through introduction of the rigid A6-A11 bond.

ABSTRACT: The development of fast-acting and highly stable insulin analogues is challenging. Insulin undergoes structural transitions essential for binding and activation of the insulin receptor (IR), but these conformational changes can also affect insulin stability. Previously, we substituted the insulin A6-A11 cystine with a rigid, non-reducible C=C linkage ("dicarba" linkage). A cis-alkene permitted the conformational flexibility of the A-chain N-terminal helix necessary for high-affinity IR binding, resulting in surprisingly rapid activity in vivo Here, we show that, unlike the rapidly acting Lys^B28Pro^B29 insulin analogue (KP insulin), cis-dicarba insulin is not inherently monomeric. We also show that cis-dicarba KP insulin lowers blood glucose

SUBMITTER: Ong SC 

PROVIDER: S-EPMC6066309 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature