Symmetric and asymmetric receptor conformation continuum induced by a new insulin

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Xiaochun Xiong - , Stanford University, University of Utah (Autor:in)
  • Alan Blakely - , University of Utah (Autor:in)
  • Jin Hwan Kim - , University of Utah (Autor:in)
  • John G. Menting - , Walter and Eliza Hall Institute of Medical Research (WEHI), University of Melbourne (Autor:in)
  • Ingmar B. Schäfer - , Max Planck Institute of Biochemistry (Autor:in)
  • Heidi L. Schubert - , University of Utah (Autor:in)
  • Rahul Agrawal - , University of Utah (Autor:in)
  • Theresia Gutmann - , Dresden International Graduate School for Interdisciplinary Life Sciences (DIGS-ILS), Deutsches Zentrum für Diabetesforschung (DZD) e.V., Paul Langerhans Institut Dresden (PLID) des Helmholtz Zentrum München (Autor:in)
  • Carlie Delaine - , Flinders University (Autor:in)
  • Yi Wolf Zhang - , Stanford University, University of Utah (Autor:in)
  • Gizem Olay Artik - , Zentrum für Membranbiochemie und Lipidforschung, Deutsches Zentrum für Diabetesforschung (DZD) e.V., Paul Langerhans Institut Dresden (PLID) des Helmholtz Zentrum München (Autor:in)
  • Allanah Merriman - , Flinders University (Autor:in)
  • Debbie Eckert - , University of Utah (Autor:in)
  • Michael C. Lawrence - , Walter and Eliza Hall Institute of Medical Research (WEHI), University of Melbourne (Autor:in)
  • Ünal Coskun - , Zentrum für Membranbiochemie und Lipidforschung, Deutsches Zentrum für Diabetesforschung (DZD) e.V., Paul Langerhans Institut Dresden (PLID) des Helmholtz Zentrum München (Autor:in)
  • Simon J. Fisher - , University of Utah, University of Kentucky (Autor:in)
  • Briony E. Forbes - , Flinders University (Autor:in)
  • Helena Safavi-Hemami - , University of Utah, Universität Kopenhagen (Autor:in)
  • Christopher P. Hill - , University of Utah (Autor:in)
  • Danny Hung Chieh Chou - , Stanford University, University of Utah (Autor:in)

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
ORCID /0000-0002-7301-7300/work/170587881

Schlagworte

ASJC Scopus Sachgebiete

Schlagwörter

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