PuSH - Publikationsserver des Helmholtz Zentrums München: Conformational quenching in an engineered lipocalin protein achieves high affinity binding to the toxin colchicine.

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Bostock, M.J. ; Kolloff, C.* ; Jerschke, E.* ; Asami, S.* ; Skerra, A.* ; Olsson, S.* ; Sattler, M.

Conformational quenching in an engineered lipocalin protein achieves high affinity binding to the toxin colchicine.

Angew. Chem.-Int. Edit.:e202515950 (2025)

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The engineered lipocalin Colchicalin binds the clinically relevant plant toxin colchicine with picomolar affinity. X-ray structures revealed major loop rearrangements at the open end of the β-barrel 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-bound Colchicalin on the picosecond-to-millisecond timescale. Fast backbone dynamics were comparable in the presence and absence of colchicine, indicating preserved secondary structure. However, large-scale fluctuations in the structurally variable loops on the microsecond-to-millisecond 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-timescale dynamics to enable specific, high-affinity ligand recognition and providing an important example for rational drug design.

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