A F420-dependent Single Domain Chemogenetic Tool for Protein De-dimerization

Abstract

Protein-protein interactions (PPIs) mediate many fu optically or chemically responsive protein domains some clinical applications. Most chemogenetic m oligomerization, of target proteins, whilst the few av gomeric protein clusters or heteromeric complexes. a homodimeric oxidoreductase from mycobacteria not present in mammals, as a bioorthogonal mon found that in the absence of F420 MSMEG_2027 f the cofactor binding site. Rearrangement of the N-t tion of the dimer. We then showed that MSMEG_20 and applied it as a tool to induce and release MAP ndamental cellular processes. Control of PPIs through has had a profound impact on basic research and ethods induce the association, i.e., dimerization or ailable dissociation approaches either break large oli-Here, we have exploited the controlled dissociation of (MSMEG_2027) by its native cofactor, F420, which is omerization switch. Using X-ray crystallography, we orms a unique domain-swapped dimer that occludes erminal helix upon F420 binding results in the dissolu-27 can be fused to proteins of interest in human cells K/ERK signalling downstream of a chimeric fibroblast growth factor receptor 1 (FGFR1) tyrosine homodimerization tool is stoichiometric and based o anism to investigate protein complexes in situ. (c) 2025 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (filipcreativecom mons.org/licenses/by/4.0)