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TitleSymmetric and asymmetric receptor conformation continuum induced by a new insulin.
Journal, issue, pagesNat Chem Biol, Vol. 18, Issue 5, Page 511-519, Year 2022
Publish dateMar 14, 2022
AuthorsXiaochun Xiong / Alan Blakely / Jin Hwan Kim / John G Menting / Ingmar B Schäfer / Heidi L Schubert / Rahul Agrawal / Theresia Gutmann / Carlie Delaine / Yi Wolf Zhang / Gizem Olay Artik / Allanah Merriman / Debbie Eckert / Michael C Lawrence / Ünal Coskun / Simon J Fisher / Briony E Forbes / Helena Safavi-Hemami / Christopher P Hill / Danny Hung-Chieh Chou /
PubMed AbstractCone 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 ...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.
External linksNat Chem Biol / PubMed:35289328 / PubMed Central
MethodsEM (single particle)
Resolution3.4 - 4.4 Å
Structure data

23949

7mqo

EMDB-23949, PDB-7mqo:
The insulin receptor ectodomain in complex with a venom hybrid insulin analog - "head" region
Method: EM (single particle) / Resolution: 3.4 Å

23950

7mqr

EMDB-23950, PDB-7mqr:
The insulin receptor ectodomain in complex with four venom hybrid insulins - symmetric conformation
Method: EM (single particle) / Resolution: 4.1 Å

23951

7mqs

EMDB-23951, PDB-7mqs:
The insulin receptor ectodomain in complex with three venom hybrid insulin molecules - asymmetric conformation
Method: EM (single particle) / Resolution: 4.4 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

Source
  • homo sapiens (human)
KeywordsHORMONE / TOXIN / insulin / receptor / venom / cone snail

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