Journal Article

PUBDB-2025-04009

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Structural insights into the substrate binding mechanism of the class I dehydratase MadB

Knospe, C. V. ; Ortiz, J. ; Reiners, J. ; Kedrov, A. ; Gertzen, C. G. W. ; Smits, S. H. J. ; Schmitt, L. (Corresponding author)

2025
Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s42003-025-08454-5

Abstract: In the battle against antimicrobial resistance, lantibiotics have emerged as promising new sources for antimicrobial drugs. Their exceptional stability is due to characteristic modifications termed (methyl-)lanthionine rings. Genome mining efforts have identified hundreds of lantibiotics by detecting gene operons, so-called biosynthetic gene clusters (BGC), which encode cysteine-rich peptides (30-50 amino acids in size) and enzymes responsible for dehydration and cyclization, catalyzing the post-translational ring formation. One such identified, class I lantibiotic is maddinglicin from Clostridium maddingley. Here, we present single particle cryo-EM structures of the dehydratase MadB in both, its apo-state and in complex with a leader peptide of maddinglicin, revealing a distinct conformational change upon substrate binding. Small-angle X-ray scattering studies elucidate the substrate binding site for the C-terminal part of maddinglicin. Furthermore, a substrate specificity analysis was performed highlighting a critical stretch of amino acids within the maddinglicin leader sequence that is crucial for binding. Here, we provide molecular insights into the conformational changes, principles of substrate recognition and ligand:protein stoichiometry of a class I lantibiotic dehydratase.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P12 (PETRA III)

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