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Xiong, X.* ; Blakely, A.* ; Kim, J.H.* ; Menting, J.G.* ; Schäfer, I.B.* ; Schubert, H.L.* ; Agrawal, R.* ; Gutmann, T. ; Delaine, C.* ; Zhang, Y.W.* ; Olay Artik, G. ; Merriman, A.* ; Eckert, D.* ; Lawrence, M.C.* ; Coskun, Ü. ; Fisher, S.J.* ; Forbes, B.E.* ; Safavi-Hemami, H.* ; Hill, C.P.* ; Chou, D.H.C.*

Symmetric and asymmetric receptor conformation continuum induced by a new insulin.

Nat. Chem. Biol. 18, 511-519 (2022)
Postprint DOI
Open Access Green
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.]
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
ISSN (print) / ISBN 1552-4450
e-ISSN 1552-4469
Quellenangaben Band: 18, Heft: 5, Seiten: 511-519 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort Basingstoke
Begutachtungsstatus Peer reviewed
Institut(e) Institute for Pancreatic Beta Cell Research (IPI)