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X\u2010ray structures revealed major loop rearrangements at the open end of the \u03b2\u2010barrel upon ligand binding, suggesting a critical role for protein dynamics. Here, we integrated solution NMR relaxation experiments with molecular dynamics (MD) simulations and Markov modelling to examine conformational dynamics in the free and ligand\u2010bound Colchicalin on the picosecond\u2010to\u2010millisecond timescale. Fast backbone dynamics were comparable in the presence and absence of colchicine, indicating preserved secondary structure. However, large\u2010scale fluctuations in the structurally variable loops on the microsecond\u2010to\u2010millisecond timescale were observed in the apo form. We identified conformational exchange between three states, binding competent, partially closed and fully closed, characterised by loop L3 rearrangements. Colchicine binding quenches these motions, indicating a strong interplay between protein dynamics and ligand recognition. Our results support conformational selection over induced fit as the binding mechanism, highlighting the critical role of slow\u2010timescale dynamics to enable specific, high\u2010affinity ligand recognition and providing an important example for rational drug design.<\/jats:p>","DOI":"10.1002\/anie.202515950","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T04:08:40Z","timestamp":1761624520000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Conformational Quenching in an Engineered Lipocalin Protein Achieves High Affinity Binding to the Toxin Colchicine"],"prefix":"10.1002","volume":"64","author":[{"given":"Mark J.","family":"Bostock","sequence":"first","affiliation":[{"name":"Bavarian NMR Center and Department of Bioscience TUM School of Natural Sciences Technical University of Munich  85748 Garching Germany"},{"name":"Institute of Structural Biology Molecular Targets and 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