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bioRxiv · 10.64898/2026.04.23.720511

Structure of a sparsely populated chimeric intermediate that facilitates fold-switching of a metamorphic protein

Nandi, B.·Sekhar, A.
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Abstract

Metamorphic proteins challenge the structure-function paradigm by switching between distinct folds. However, the conformational states sampled along the fold-switching pathway have remained elusive because they are transient and unstable. Using multinuclear chemical exchange saturation transfer and relaxation dispersion nuclear magnetic resonance, combined with chemical shift-based structure determination and protein engineering, we visualized the atomic-resolution structure of an invisible state of the metamorphic chemokine lymphotactin. This state is a chimera that integrates the secondary and tertiary structure of one fold with the quaternary assembly of the other. Locking lymphotactin into a single conformation abolishes access to this state, supporting its role as an on-pathway intermediate in metamorphosis. The stabilization of such hybrid intermediates is likely to have facilitated the evolution of fold switching and represent a powerful strategy for protein design.

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Nandi, B., Sekhar, A.. 2026-04-26. Structure of a sparsely populated chimeric intermediate that facilitates fold-switching of a metamorphic protein. https://doi.org/10.64898/2026.04.23.720511

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