Symmetric and asymmetric receptor conformation continuum induced by a new insulin

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

Abstract

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.]

Details

OriginalspracheEnglisch
Seiten (von - bis)511-519
Seitenumfang9
FachzeitschriftNature chemical biology
Jahrgang18
Ausgabenummer5
PublikationsstatusVeröffentlicht - Mai 2022
Peer-Review-StatusJa

Externe IDs

PubMed 35289328
Scopus 85126205351

Schlagworte

ASJC Scopus Sachgebiete

Schlagwörter

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