8SBD

Cryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments

Summary for 8SBD

• Entry DOI: 10.2210/pdb8sbd/pdb
• EMDB information: 40305
• Descriptor: Insulin B chain, Insulin A chain (2 entities in total)
• Functional Keywords: amyloid-like fibril, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 32
• Total formula weight: 93082.42

Authors

Wang, L.W.,Hall, C.,Uchikawa, E.,Chen, D.L.,Choi, E.,Zhang, X.W.,Bai, X.C. (deposition date: 2023-04-03, release date: 2023-08-30, Last modification date: 2024-10-23)

Primary citation

Wang, L.,Hall, C.E.,Uchikawa, E.,Chen, D.,Choi, E.,Zhang, X.,Bai, X.C.
Structural basis of insulin fibrillation.
Sci Adv, 9:eadi1057-eadi1057, 2023

PubMed Abstract: Insulin is a hormone responsible for maintaining normal glucose levels by activating insulin receptor (IR) and is the primary treatment for diabetes. However, insulin is prone to unfolding and forming cross-β fibers. Fibrillation complicates insulin storage and therapeutic application. Molecular details of insulin fibrillation remain unclear, hindering efforts to prevent fibrillation process. Here, we characterized insulin fibrils using cryo-electron microscopy (cryo-EM), showing multiple forms that contain one or more of the protofilaments containing both the A and B chains of insulin linked by disulfide bonds. We solved the cryo-EM structure of one of the fibril forms composed of two protofilaments at 3.2-Å resolution, which reveals both the β sheet conformation of the protofilament and the packing interaction between them that underlie the fibrillation. On the basis of this structure, we designed several insulin mutants that display reduced fibrillation while maintaining native IR signaling activity. These designed insulin analogs may be developed into more effective therapeutics for type 1 diabetes.

PubMed: 37713485
DOI: 10.1126/sciadv.adi1057

Experimental method

ELECTRON MICROSCOPY (3.2 Å)