2. Academic Validation
  3. Cryo-EM structure and inhibitor design of human IAPP (amylin) fibrils

Cryo-EM structure and inhibitor design of human IAPP (amylin) fibrils

  • Nat Struct Mol Biol. 2020 Jul;27(7):653-659. doi: 10.1038/s41594-020-0435-3.
Qin Cao 1,  David R Boyer 1,  Michael R Sawaya 1,  Peng Ge 2,  David S Eisenberg 3
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry and Biological Chemistry, UCLA-DOE Institute, Molecular Biology Institute, and Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA, USA.
  • 2 California NanoSystem Institute, University of California, Los Angeles, Los Angeles, CA, USA.
  • 3 Department of Chemistry and Biochemistry and Biological Chemistry, UCLA-DOE Institute, Molecular Biology Institute, and Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA, USA. [email protected].
PMID: 32541896 DOI: 10.1038/s41594-020-0435-3
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 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.

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