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We provide evidence indicating that the mechanism behind the antiamyloidogenic effect of PcTS is correlated with the trapping of prefibrillar AS species during the early stages of the assembly process. By using NMR spectroscopy, we have located the primary binding region for PcTS to a specific site in the N terminus of AS, involving the amino acid Tyr-39 as the anchoring residue. Moreover, the residue-specific structural characterization of the AS-PcTS complex provided the basis for the rational design of nonamyloidogenic species of AS, highlighting the role of aromatic interactions in driving AS amyloid assembly. A comparative analysis with other proteins involved in neurodegenerative disorders reveals that aromatic recognition interfaces might constitute a key structural element to target their aggregation pathways. These findings emphasize the use of aggregation inhibitors as molecular probes to assess structural and toxic mechanisms related to amyloid formation and the potential of small molecules as therapeutics for amyloid-related pathologies.<\/jats:p>","DOI":"10.1073\/pnas.0902603106","type":"journal-article","created":{"date-parts":[[2009,11,30]],"date-time":"2009-11-30T22:19:59Z","timestamp":1259619599000},"page":"21057-21062","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":105,"title":["Structural and mechanistic basis behind the inhibitory interaction of PcTS on \u03b1-synuclein amyloid fibril formation"],"prefix":"10.1073","volume":"106","author":[{"given":"Gonzalo R.","family":"Lamberto","sequence":"first","affiliation":[{"name":"Instituto de Biolog\u00eda Molecular y Celular de Rosario, Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK Rosario, Argentina;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9s","family":"Binolfi","sequence":"additional","affiliation":[{"name":"Instituto de Biolog\u00eda Molecular y Celular de Rosario, Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK Rosario, Argentina;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda L.","family":"Orcellet","sequence":"additional","affiliation":[{"name":"Instituto de Biolog\u00eda Molecular y Celular de Rosario, Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK Rosario, Argentina;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos W.","family":"Bertoncini","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Zweckstetter","sequence":"additional","affiliation":[{"name":"Department of Nuclear Magnetic Resonance-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, D-37077 G\u00f6ttingen, Germany; and"},{"name":"Deutsche Forschungsgemeinschaft Center for the Molecular Physiology of the Brain, D-37077 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Griesinger","sequence":"additional","affiliation":[{"name":"Department of Nuclear Magnetic Resonance-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, D-37077 G\u00f6ttingen, Germany; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio O.","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Instituto de Biolog\u00eda Molecular y Celular de Rosario, Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK Rosario, Argentina;"},{"name":"Department of Nuclear Magnetic Resonance-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, D-37077 G\u00f6ttingen, Germany; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,12,15]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2008.02.011"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/42166"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.276.5321.2045"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0298-106"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M008919200"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600211"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja0561901"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0407146102"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1021\/jp068604y"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(97)01290-8"},{"key":"e_1_3_3_11_2","first-page":"1","article-title":"Cognitive-performance recovery of Alzheimer's disease model mice by modulation of early soluble amyloidal assemblies","volume":"47","author":"Frydman-Marom A","year":"2008","unstructured":"A Frydman-Marom, et al., Cognitive-performance recovery of Alzheimer's disease model mice by modulation of early soluble amyloidal assemblies. 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