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| Title | Cryo-EM structure and inhibitor design of human IAPP (amylin) fibrils. |
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| Journal, issue, pages | Nat Struct Mol Biol, Vol. 27, Issue 7, Page 653-659, Year 2020 |
| Publish date | Jun 15, 2020 |
 Authors | Qin Cao / David R Boyer / Michael R Sawaya / Peng Ge / David S Eisenberg /  |
| PubMed Abstract | Human islet amyloid polypeptide (hIAPP) functions as a glucose-regulating hormone but deposits as amyloid fibrils in more than 90% of patients with type II diabetes (T2D). Here we report the cryo-EM ...Human islet amyloid polypeptide (hIAPP) functions as a glucose-regulating hormone but deposits as amyloid fibrils in more than 90% of patients with type II diabetes (T2D). Here we report the cryo-EM structure of recombinant full-length hIAPP fibrils. The fibril is composed of two symmetrically related protofilaments with ordered residues 14-37. Our hIAPP fibril structure (i) supports the previous hypothesis that residues 20-29 constitute the core of the hIAPP amyloid; (ii) suggests a molecular mechanism for the action of the hIAPP hereditary mutation S20G; (iii) explains why the six residue substitutions in rodent IAPP prevent aggregation; and (iv) suggests regions responsible for the observed hIAPP cross-seeding with β-amyloid. Furthermore, we performed structure-based inhibitor design to generate potential hIAPP aggregation inhibitors. Four of the designed peptides delay hIAPP aggregation in vitro, providing a starting point for the development of T2D therapeutics and proof of concept that the capping strategy can be used on full-length cryo-EM fibril structures. |
 External links | Nat Struct Mol Biol / PubMed:32541896 / PubMed Central |
| Methods | EM (helical sym.) |
| Resolution | 3.4 Å |
| Structure data | EMDB-21410, PDB-6vw2: |
| Source |
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 Keywords | PROTEIN FIBRIL / hIAPP / type II diabetes / amyloid |
homo sapiens (human)
saccharomyces cerevisiae (strain atcc 204508 / s288c) (yeast)