7SL4

Full-length insulin receptor bound with site 2 binding deficient mutant insulin (B-L17R) -- asymmetric conformation

Summary for 7SL4

• Entry DOI: 10.2210/pdb7sl4/pdb
• EMDB information: 25188 25189 25190 25191
• Descriptor: Insulin receptor, Insulin B chain, Insulin A chain (3 entities in total)
• Functional Keywords: insulin receptor, site 1 binding deficient mutant insulin, signaling protein, signaling protein-hormone complex, signaling protein/hormone
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 6
• Total formula weight: 323304.41

Authors

Bai, X.C.,Choi, E. (deposition date: 2021-10-22, release date: 2022-03-30, Last modification date: 2022-04-27)

Primary citation

Li, J.,Park, J.,Mayer, J.P.,Webb, K.J.,Uchikawa, E.,Wu, J.,Liu, S.,Zhang, X.,Stowell, M.H.B.,Choi, E.,Bai, X.C.
Synergistic activation of the insulin receptor via two distinct sites.
Nat.Struct.Mol.Biol., 29:357-368, 2022

PubMed Abstract: Insulin receptor (IR) signaling controls multiple facets of animal physiology. Maximally four insulins bind to IR at two distinct sites, termed site-1 and site-2. However, the precise functional roles of each binding event during IR activation remain unresolved. Here, we showed that IR incompletely saturated with insulin predominantly forms an asymmetric conformation and exhibits partial activation. IR with one insulin bound adopts a Γ-shaped conformation. IR with two insulins bound assumes a Ƭ-shaped conformation. One insulin binds at site-1 and another simultaneously contacts both site-1 and site-2 in the Ƭ-shaped IR dimer. We further show that concurrent binding of four insulins to sites-1 and -2 prevents the formation of asymmetric IR and promotes the T-shaped symmetric, fully active state. Collectively, our results demonstrate how the synergistic binding of multiple insulins promotes optimal IR activation.

PubMed: 35361965
DOI: 10.1038/s41594-022-00750-6

Experimental method

ELECTRON MICROSCOPY (5 Å)