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Whereas high crystallographic temperature factors can denote either static disorder or motion, even moieties with very low B\u2010factors can be subject to vivid motion between symmetry\u2010related sites. Here we report the experimental identification of internal \u03bcs timescale dynamics of a high\u2010affinity, natural\u2010abundance ligand tightly bound to the enzyme human carbonic anhydrase\u2005II (hCAII) even within a crystalline lattice. The rotamer jumps of the ligand's benzene group manifest themselves both, in solution and fast magic\u2010angle spinning solid\u2010state NMR\n                    <jats:sup>1<\/jats:sup>\n                    H\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sub>1\u03c1<\/jats:sub>\n                    relaxation dispersion, for which we obtain further mechanistic insights from molecular\u2010dynamics (MD) simulations. The experimental confirmation of rotameric jumps in bound ligands within proteins in solution or the crystalline state may improve understanding of host\u2010guest interactions in biology and supra\u2010molecular chemistry and may facilitate medicinal chemistry for future drug campaigns.\n                  <\/jats:p>","DOI":"10.1002\/anie.202313947","type":"journal-article","created":{"date-parts":[[2023,11,17]],"date-time":"2023-11-17T02:58:34Z","timestamp":1700189914000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Microsecond Timescale Conformational Dynamics of a Small\u2010Molecule Ligand within the Active Site of a Protein"],"prefix":"10.1002","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3736-7888","authenticated-orcid":false,"given":"Julia","family":"Kotschy","sequence":"first","affiliation":[{"name":"Department of Chemistry and Chemical Biology TU Dortmund University  Otto-Hahn-Str.\u20054a 44227 Dortmund Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2738-8263","authenticated-orcid":false,"given":"Benedikt","family":"S\u00f6ldner","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology TU Dortmund University  Otto-Hahn-Str.\u20054a 44227 Dortmund Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2819-6282","authenticated-orcid":false,"given":"Himanshu","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology TU Dortmund University  Otto-Hahn-Str.\u20054a 44227 Dortmund Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8137-9344","authenticated-orcid":false,"given":"Suresh K.","family":"Vasa","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology TU Dortmund University  Otto-Hahn-Str.\u20054a 44227 Dortmund Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8983-2935","authenticated-orcid":false,"given":"Rasmus","family":"Linser","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology TU Dortmund University  Otto-Hahn-Str.\u20054a 44227 Dortmund Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,12,15]]},"reference":[{"key":"e_1_2_3_1_1","unstructured":"\u00a0"},{"key":"e_1_2_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0076-6879(86)31050-4"},{"key":"e_1_2_3_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200701169"},{"key":"e_1_2_3_4_1","first-page":"98","volume":"279","author":"Bacon G. 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