Biochemistry and Pharmacology - Research Publications

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Mechanism of NanR gene repression and allosteric induction of bacterial sialic acid metabolism

Horne, CR ; Venugopal, H ; Panjikar, S ; Wood, DM ; Henrickson, A ; Brookes, E ; North, RA ; Murphy, JM ; Friemann, R ; Griffin, MDW ; Ramm, G ; Demeler, B ; Dobson, RCJ (NATURE PORTFOLIO, 2021-03-31)

Bacteria respond to environmental changes by inducing transcription of some genes and repressing others. Sialic acids, which coat human cell surfaces, are a nutrient source for pathogenic and commensal bacteria. The Escherichia coli GntR-type transcriptional repressor, NanR, regulates sialic acid metabolism, but the mechanism is unclear. Here, we demonstrate that three NanR dimers bind a (GGTATA)3-repeat operator cooperatively and with high affinity. Single-particle cryo-electron microscopy structures reveal the DNA-binding domain is reorganized to engage DNA, while three dimers assemble in close proximity across the (GGTATA)3-repeat operator. Such an interaction allows cooperative protein-protein interactions between NanR dimers via their N-terminal extensions. The effector, N-acetylneuraminate, binds NanR and attenuates the NanR-DNA interaction. The crystal structure of NanR in complex with N-acetylneuraminate reveals a domain rearrangement upon N-acetylneuraminate binding to lock NanR in a conformation that weakens DNA binding. Our data provide a molecular basis for the regulation of bacterial sialic acid metabolism.