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U.S.A."],"published-print":{"date-parts":[[2024,6,4]]},"abstract":"<jats:p>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 \u03b2\u2010strands. 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.<\/jats:p>","DOI":"10.1073\/pnas.2401458121","type":"journal-article","created":{"date-parts":[[2024,5,29]],"date-time":"2024-05-29T12:17:16Z","timestamp":1716985036000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":33,"title":["Atomic resolution structure of full-length human insulin fibrils"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6226-1570","authenticated-orcid":false,"given":"Saba","family":"Suladze","sequence":"first","affiliation":[{"name":"Bavarian Nuclear Magnetic Resonance Center at the Department of Biosciences, School of Natural Sciences, Technische Universit\u00e4t M\u00fcnchen, Garching 85747, Germany"},{"name":"Helmholtz-Zentrum M\u00fcnchen, Deutsches 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