Summary information and primary citation
- PDB-id
-
9jf9;
DSSR-derived features in text and
JSON formats
- Class
- membrane protein
- Method
- cryo-EM (6.26 Å)
- Summary
- Human insulin receptor bound with a62-dimer,
pseudo-arrowhead conformation
- Reference
-
Kim J, Na H, Choi SY, Oh EJ, Lee H, Ryu SH, Yunn NO, Cho
Y (2025): "Structural
mechanism of insulin receptor activation by a dimeric
aptamer agonist." Exp.Mol.Med.,
57, 1506-1518. doi: 10.1038/s12276-025-01494-1.
- Abstract
- Insulin binding to the insulin receptor (IR) triggers
signaling pathways that regulate glucose uptake and cell
growth. In previous work, we identified a DNA aptamer, A62,
which partially activates the IR. During engineering
aptamers for improved in vivo stability, we discovered that
crosslinking two A62 aptamers with linkers of varying
lengths led to full phosphorylation of the IR, although
activation remained selective to the AKT pathway. Here, to
elucidate the mechanism behind this aptamer-induced full
activation of the IR, we determined the structure of the IR
in complex with a dimeric form of A62 (A62D) linked by an
eight-nucleotide connector. We identified three distinct
conformations of the IR: arrowhead-shaped,
pseudo-arrowhead-shaped and pseudo-gamma-shaped. The
pseudo-gamma-shaped conformation closely resembles the
structure of a fully active IR bound by a single insulin
molecule. In these configurations, only one A62 monomer
(A62M) within the A62D dimer binds to the IR dimer. This
binding brings the IR monomers into close proximity,
promoting intermolecular trans-phosphorylation. Our
findings provide valuable structural insights for the
development of novel therapeutic strategies targeting the
IR.
