6HN4

Leucine-zippered human insulin receptor ectodomain with single bound insulin - "lower" membrane-proximal part

Summary for 6HN4

• Entry DOI: 10.2210/pdb6hn4/pdb
• EMDB information: 0246
• Descriptor: Insulin receptor,Insulin receptor,General control protein GCN4, 2-acetamido-2-deoxy-beta-D-glucopyranose (2 entities in total)
• Functional Keywords: insulin, insulin receptor ectodomain, signal transdution, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 214783.67

Authors

Weis, F.,Menting, J.G.,Margetts, M.B.,Chan, S.J.,Xu, Y.,Tennagels, N.,Wohlfart, P.,Langer, T.,Mueller, C.W.,Dreyer, M.K.,Lawrence, M.C. (deposition date: 2018-09-14, release date: 2018-11-21, Last modification date: 2022-03-30)

Primary citation

Weis, F.,Menting, J.G.,Margetts, M.B.,Chan, S.J.,Xu, Y.,Tennagels, N.,Wohlfart, P.,Langer, T.,Muller, C.W.,Dreyer, M.K.,Lawrence, M.C.
The signalling conformation of the insulin receptor ectodomain.
Nat Commun, 9:4420-4420, 2018

PubMed Abstract: Understanding the structural biology of the insulin receptor and how it signals is of key importance in the development of insulin analogs to treat diabetes. We report here a cryo-electron microscopy structure of a single insulin bound to a physiologically relevant, high-affinity version of the receptor ectodomain, the latter generated through attachment of C-terminal leucine zipper elements to overcome the conformational flexibility associated with ectodomain truncation. The resolution of the cryo-electron microscopy maps is 3.2 Å in the insulin-binding region and 4.2 Å in the membrane-proximal region. The structure reveals how the membrane proximal domains of the receptor come together to effect signalling and how insulin's negative cooperativity of binding likely arises. Our structure further provides insight into the high affinity of certain super-mitogenic insulins. Together, these findings provide a new platform for insulin analog investigation and design.

PubMed: 30356040
DOI: 10.1038/s41467-018-06826-6

Experimental method

ELECTRON MICROSCOPY (4.2 Å)