Two-dimensional infrared spectroscopy reveals the complex behaviour of an amyloid fibril inhibitor

Chris T. Middleton, Peter Marek, Ping Cao, Chi Cheng Chiu, Sadanand Singh, Ann Marie Woys, Juan J. De Pablo, Daniel P. Raleigh, Martin T. Zanni

Research output: Contribution to journalArticlepeer-review

141 Citations (Scopus)


Amyloid formation has been implicated in the pathology of over 20 human diseases, but the rational design of amyloid inhibitors is hampered by a lack of structural information about amyloid-inhibitor complexes. We use isotope labelling and two-dimensional infrared spectroscopy to obtain a residue-specific structure for the complex of human amylin (the peptide responsible for islet amyloid formation in type 2 diabetes) with a known inhibitor (rat amylin). Based on its sequence, rat amylin should block formation of the C-terminal β-sheet, but at 8 h after mixing, rat amylin blocks the N-terminal β-sheet instead. At 24 h after mixing, rat amylin blocks neither β-sheet and forms its own β-sheet, most probably on the outside of the human fibrils. This is striking, because rat amylin is natively disordered and not previously known to form amyloid β-sheets. The results show that even seemingly intuitive inhibitors may function by unforeseen and complex structural processes.

Original languageEnglish
Pages (from-to)355-360
Number of pages6
JournalNature Chemistry
Issue number5
Publication statusPublished - 2012 May

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)


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