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Nuclear magnetic resonance spectroscopy provides a unique opportunity to achieve detailed atom-resolved information toward this ambitious goal. We present here a set of differently functionalized calix[4]arene-based multivalent ligands designed to target different regions of the well-characterized intrinsically disordered protein \u03b1-synuclein. Dedicated NMR experiments extended the analysis from backbone to side-chain nuclear spins, thus enabling the atom-resolved identification of short-range contacts between the calixarene ligands and methyl or aromatic groups of the protein surface, and revealing how these interactions refine the electrostatically driven association within different lysine-rich motifs. This approach provides a comprehensive description of how the macrocycles recognize and bind the target protein, offering a basis for the rational design of ligands capable of modulating protein function.<\/jats:p>","DOI":"10.1021\/jacs.6c16561","type":"journal-article","created":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T13:02:18Z","timestamp":1792674138000},"source":"Crossref","is-referenced-by-count":0,"title":["Toward the Rational\nDesign of Tailored Ligands for\nIntrinsically Disordered Proteins through NMR"],"prefix":"10.1021","author":[{"given":"Cristina","family":"Ciabini","sequence":"first","affiliation":[{"name":"University of Florence , , , ,","place":["Sesto Fiorentino, FI, Italy, 50019"]},{"name":"University of Florence , , , ,","place":["Sesto Fiorentino, FI, Italy, 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, , , ,","place":["Sesto Fiorentino, FI, Italy, 50019"]},{"name":"University of Florence , , , ,","place":["Sesto Fiorentino, FI, Italy, 50019"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"Bonini","sequence":"additional","affiliation":[{"name":"University of Florence , , , ,","place":["Sesto Fiorentino, FI, Italy, 50019"]},{"name":"University of Florence , , , ,","place":["Sesto Fiorentino, FI, Italy, 50019"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Cremonini","sequence":"additional","affiliation":[{"name":"University of Parma , , ,","place":["Parma, Italy, 43124"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9899-0836","authenticated-orcid":true,"given":"Francesca","family":"Clemente","sequence":"additional","affiliation":[{"name":"University of Florence , , , ,","place":["Sesto Fiorentino, FI, Italy, 50019"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6766-4624","authenticated-orcid":true,"given":"Francesca","family":"Cardona","sequence":"additional","affiliation":[{"name":"University of Florence , , , ,","place":["Sesto Fiorentino, FI, Italy, 50019"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1914-2338","authenticated-orcid":true,"given":"Stefano","family":"Volpi","sequence":"additional","affiliation":[{"name":"University of Parma , , ,","place":["Parma, Italy, 43124"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0985-4331","authenticated-orcid":true,"given":"Laura","family":"Baldini","sequence":"additional","affiliation":[{"name":"University of Parma , , ,","place":["Parma, Italy, 43124"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0531-9865","authenticated-orcid":true,"given":"Francesco","family":"Sansone","sequence":"additional","affiliation":[{"name":"University of Parma , , ,","place":["Parma, Italy, 43124"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7755-0885","authenticated-orcid":true,"given":"Roberta","family":"Pierattelli","sequence":"additional","affiliation":[{"name":"University of Florence , , , ,","place":["Sesto Fiorentino, FI, Italy, 50019"]},{"name":"University of Florence , , , ,","place":["Sesto Fiorentino, FI, Italy, 50019"]},{"name":"Consorzio Interuniversitario Risonanze Magnetiche Metallo Proteine (CIRMMP) , ,","place":["Sesto Fiorentino, Italy, 50019"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6018-9090","authenticated-orcid":true,"given":"Isabella 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Neurosci."},{"issue":"10","key":"2026102209021117300_cit44","doi-asserted-by":"publisher","first-page":"1649","DOI":"10.1002\/cbic.200800035","article-title":"Calix[n]arene-based\nglycoclusters: Bioactivity of thiourea-linked galactose\/lactose moieties\nas Inhibitors of binding of medically relevant lectins to a glycoprotein\nand cell-surface glycoconjugates and selectivity among human Adhesion\/Growth-Regulatory\nGalectins","volume":"9","author":"Andre\u0301","year":"2008","journal-title":"ChemBioChem"},{"issue":"26","key":"2026102209021117300_cit45","doi-asserted-by":"publisher","first-page":"4340","DOI":"10.1039\/C3OB40515J","article-title":"Picomolar inhibition\nof Cholera Toxin by a pentavalent ganglioside GM1os-Calix[5]Arene","volume":"11","author":"Garcia-Hartjes","year":"2013","journal-title":"Org. Biomol Chem."},{"issue":"7","key":"2026102209021117300_cit46","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1038\/nchem.1342","article-title":"Protein\ncamouflage in cytochrome c\u2013calixarene complexes","volume":"4","author":"McGovern","year":"2012","journal-title":"Nat. Chem."},{"issue":"4","key":"2026102209021117300_cit47","doi-asserted-by":"publisher","first-page":"2467","DOI":"10.1021\/acs.cgd.8b00092","article-title":"Phosphonated calixarene as a \u201cMolecular Glue\u201d\nfor protein crystallization","volume":"18","author":"Alex","year":"2018","journal-title":"Cryst. 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