8RVT

Structure of full-length human insulin fibrils

Summary for 8RVT

• Entry DOI: 10.2210/pdb8rvt/pdb
• NMR Information: BMRB: 51867
• Descriptor: Insulin A chain, Insulin B chain (2 entities in total)
• Functional Keywords: diabetes, amyloid-like fibril, protein fibril
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 10
• Total formula weight: 29088.25

Authors

Bardiaux, B.,Suladze, S.,Reif, B. (deposition date: 2024-02-02, release date: 2024-05-29, Last modification date: 2024-11-13)

Primary citation

Suladze, S.,Sarkar, R.,Rodina, N.,Bokvist, K.,Krewinkel, M.,Scheps, D.,Nagel, N.,Bardiaux, B.,Reif, B.
Atomic resolution structure of full-length human insulin fibrils.
Proc.Natl.Acad.Sci.USA, 121:e2401458121-e2401458121, 2024

PubMed Abstract: Patients with type 1 diabetes mellitus who are dependent on an external supply of insulin develop insulin-derived amyloidosis at the sites of insulin injection. A major component of these plaques is identified as full-length insulin consisting of the two chains A and B. While there have been several reports that characterize insulin misfolding and the biophysical properties of the fibrils, atomic-level information on the insulin fibril architecture remains elusive. We present here an atomic resolution structure of a monomorphic insulin amyloid fibril that has been determined using magic angle spinning solid-state NMR spectroscopy. The structure of the insulin monomer yields a U-shaped fold in which the two chains A and B are arranged in parallel to each other and are oriented perpendicular to the fibril axis. Each chain contains two β-strands. We identify two hydrophobic clusters that together with the three preserved disulfide bridges define the amyloid core structure. The surface of the monomeric amyloid unit cell is hydrophobic implicating a potential dimerization and oligomerization interface for the assembly of several protofilaments in the mature fibril. The structure provides a starting point for the development of drugs that bind to the fibril surface and disrupt secondary nucleation as well as for other therapeutic approaches to attenuate insulin aggregation.

PubMed: 38809711
DOI: 10.1073/pnas.2401458121

Experimental method

SOLID-STATE NMR