7MQS

The insulin receptor ectodomain in complex with three venom hybrid insulin molecules - asymmetric conformation

Summary for 7MQS

• Entry DOI: 10.2210/pdb7mqs/pdb
• Related: 7MQO 7MQR
• EMDB information: 23951
• Descriptor: Isoform Short of Insulin receptor, Insulin A chain, Insulin B chain (3 entities in total)
• Functional Keywords: insulin, receptor, venom, cone snail, hormone, toxin
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 225087.56

Authors

Blakely, A.D.,Xiong, X.,Kim, J.H.,Menting, J.,Schafer, I.B.,Schubert, H.L.,Agrawal, R.,Gutmann, T.,Delaine, C.,Zhang, Y.,Artik, G.O.,Merriman, A.,Eckert, D.,Lawrence, M.C.,Coskun, U.,Fisher, S.J.,Forbes, B.E.,Safavi-Hemami, H.,Hill, C.P.,Chou, D.H.C. (deposition date: 2021-05-06, release date: 2022-03-16, Last modification date: 2024-10-23)

Primary citation

Xiong, X.,Blakely, A.,Kim, J.H.,Menting, J.G.,Schafer, I.B.,Schubert, H.L.,Agrawal, R.,Gutmann, T.,Delaine, C.,Zhang, Y.W.,Artik, G.O.,Merriman, A.,Eckert, D.,Lawrence, M.C.,Coskun, U.,Fisher, S.J.,Forbes, B.E.,Safavi-Hemami, H.,Hill, C.P.,Chou, D.H.
Symmetric and asymmetric receptor conformation continuum induced by a new insulin.
Nat.Chem.Biol., 18:511-519, 2022

PubMed 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.

PubMed: 35289328
DOI: 10.1038/s41589-022-00981-0

Experimental method

ELECTRON MICROSCOPY (4.4 Å)