9JHS

Human insulin receptor bound with A62-dimer, arrowhead conformation

Summary for 9JHS

• Entry DOI: 10.2210/pdb9jhs/pdb
• EMDB information: 61490
• Descriptor: Insulin receptor, DNA/RNA (5'-D(P*CP*(AF2)P*(DUZ)P*(DUZ)P*AP*(CFZ)P*GP*(CFZ)P*A)-R(P*(85Y)P*(OMG))-D(P*(AF2))-R(P*(OMG))-D(P*(DUZ)P*C)-R(P*(85Y))-D(P*AP*GP*(AF2))-R(P*(85Y)P*(OMC))-D(P*(CFZ)P*GP*(DUZ))-3') (2 entities in total)
• Functional Keywords: diabetes, signaling, agonist, aptamer, complex, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 226679.25

Authors

Kim, J.,Na, H.,Yunn, N.,Ryu, S.,Cho, Y. (deposition date: 2024-09-10, release date: 2025-07-16)

Primary citation

Kim, J.,Na, H.,Choi, S.Y.,Oh, E.J.,Lee, H.,Ryu, S.H.,Yunn, N.O.,Cho, Y.
Structural mechanism of insulin receptor activation by a dimeric aptamer agonist.
Exp.Mol.Med., 2025

PubMed 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.

PubMed: 40603733
DOI: 10.1038/s12276-025-01494-1

Experimental method

ELECTRON MICROSCOPY (5.02 Å)