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bioRxiv · 10.1101/2024.12.18.628861

Mechanism of catalytic apparatus of human chitotriosidase-1 and its dual inactivation mode by the first-in-class OATD-01 inhibitor.

Niedzialek, D.·Wieczorek, G.·Drzewicka, K.·Antosiewicz, A.·Milewski, M.·Bartoszewicz, A.·Olczak, J.·Zaslona, Z.
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Abstract

Despite extensive research over the past three decades, there are still uncertainties regarding the catalytic mechanism of human chitotriosidase-1. To fill the gap, we reanalysed the structural information available for this enzyme. Based on the existing and new experimental data, complemented by multi-scale simulations, we modelled the full-length structure of human chitotriosidase-1 and proposed the general model of its catalytic mechanism. We have elucidated the catalytic role of the four highly conserved structural motifs present in glycoside hydrolases 18 family and demonstrated the impact of ions on achieving optimal catalytic conditions. Furthermore, we have identified distinct mechanical motions within the catalytic domain that collectively facilitate the catalysis. Finally, we demonstrate how subtle dynamical changes observed within the active site upon binding of the OATD-01 inhibitor correspond to long-range effects that are transmitted across enzyme subunits, leading to profound biological consequences.

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Niedzialek, D., Wieczorek, G., Drzewicka, K., Antosiewicz, A., Milewski, M., Bartoszewicz, A., Olczak, J., Zaslona, Z.. 2024-12-21. Mechanism of catalytic apparatus of human chitotriosidase-1 and its dual inactivation mode by the first-in-class OATD-01 inhibitor.. https://doi.org/10.1101/2024.12.18.628861

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