8QJ1

Cryo-EM structure of human islet amyloid polypeptide (hIAPP) mutant A25P, polymorph 1

8QJ1 の概要

• エントリーDOI: 10.2210/pdb8qj1/pdb
• EMDBエントリー: 18441
• 分子名称: Islet amyloid polypeptide (1 entity in total)
• 機能のキーワード: amyloid, protein fibril
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 15
• 化学式量合計: 59000.24

構造登録者

Ooi, S.A.,Valli, D.,Maj, M. (登録日: 2023-09-12, 公開日: 2025-05-21, 最終更新日: 2026-02-11)

主引用文献

Ooi, S.A.,Valli, D.,Kuska, M.I.,Mari, H.,Chaudhary, H.,Wahlgren, W.Y.,Westenhoff, S.,Tietze, A.A.,Novials, A.,Servitja, J.M.,Maj, M.
Cryo-EM exposes diverse polymorphism in IAPP mutants to guide the rational design of peptide-based therapeutics.
J.Mol.Biol., 437:169405-169405, 2025

PubMed Abstract: In the pursuit of potential therapeutic agents for type 2 diabetes, non-amyloidogenic forms of the human Islet Amyloid Polypeptide (hIAPP) containing site-specific mutations are of significant interest. In the present study, we dissect the three proline mutations present in the core region of the non-amyloidogenic rat IAPP into single-point mutations at A25P, S28P, and S29P sites. We apply high-resolution cryo-electron microscopy and solve the structures of 6 polymorphs formed by these mutants, revealing the peptide's self-assembly patterns and identifying critical interactions that reinforce these structures in the presence of the β-sheet breaker. A unique trimeric aggregate with C3 symmetry was identified in the A25P mutant, which we resolved with a 3.05 Å resolution, while asymmetric trimeric assemblies were observed in the other mutants. Guided by the high-resolution structural models of A25P and S28P fibrils obtained in our study, we successfully designed novel non-amyloidogenic mutants of IAPP with potential therapeutic value. Our findings demonstrate the immense potential of structure-based approaches in developing effective therapeutics against amyloid diseases.

PubMed: 40850490
DOI: 10.1016/j.jmb.2025.169405

実験手法

ELECTRON MICROSCOPY (3.06 Å)