Symmetric and asymmetric receptor conformation continuum induced by a new insulin

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung



Cone snail venoms contain a wide variety of bioactive peptides, including insulin-like molecules with distinct structural features, binding modes and biochemical properties. Here, we report an active humanized cone snail venom insulin with an elongated A chain and a truncated B chain, and use cryo-electron microscopy (cryo-EM) and protein engineering to elucidate its interactions with the human insulin receptor (IR) ectodomain. We reveal how an extended A chain can compensate for deletion of B-chain residues, which are essential for activity of human insulin but also compromise therapeutic utility by delaying dissolution from the site of subcutaneous injection. This finding suggests approaches to developing improved therapeutic insulins. Curiously, the receptor displays a continuum of conformations from the symmetric state to a highly asymmetric low-abundance structure that displays coordination of a single humanized venom insulin using elements from both of the previously characterized site 1 and site 2 interactions. [Figure not available: see fulltext.]


Seiten (von - bis)511-519
FachzeitschriftNature chemical biology
PublikationsstatusVeröffentlicht - Mai 2022

Externe IDs

PubMed 35289328
Scopus 85126205351


ASJC Scopus Sachgebiete


  • Cryoelectron Microscopy, Humans, Insulin/metabolism, Mollusk Venoms/chemistry, Peptides, Protein Conformation