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

Atomic resolution structure of a transient, hybrid intermediate in lymphotactin fold-switching reveals a chimera combining features of two distinct folds.

• Why it matters: Understanding the conformational states involved in fold-switching is crucial because these states are transient and unstable, challenging the single-sequence-structure paradigm and limiting insights into metamorphic proteins' mechanisms and evolution.
• What they did: The authors used multinuclear chemical exchange saturation transfer, relaxation dispersion NMR, chemical shift-based structure determination, and protein engineering to visualize this "invisible" intermediate state of lymphotactin, which is stabilized as a chimera.
• The result: Locking lymphotactin into a single conformation prevents access to this intermediate, supporting its role in fold-switching, and highlighting the potential of stabilizing hybrid intermediates for protein design and understanding metamorphosis.