9WXS

Silver-bound E.coli Malate dehydrogenase (C251S)

Summary for 9WXS

• Entry DOI: 10.2210/pdb9wxs/pdb
• Related: 5Z3W
• Descriptor: Malate dehydrogenase, SILVER ION (3 entities in total)
• Functional Keywords: dehydrogenase, cytosolic protein
• Biological source: Escherichia coli K-12
• Total number of polymer chains: 4
• Total formula weight: 129839.92

Authors

Wang, H.,Wang, M.,Sun, H. (deposition date: 2025-09-25, release date: 2025-10-29, Last modification date: 2025-12-03)

Primary citation

Wang, H.,Wang, M.,Yang, X.,Yan, A.,Hao, Q.,Li, H.,Sun, H.
Unprecedented allosteric inhibition of E. coli malate dehydrogenase by silver(i) from atomic resolution analysis.
Chem Sci, 16:21379-21385, 2025

PubMed Abstract: Metal ions may functionally inhibit metalloproteins either replacement of intact metal cofactors or binding to allosteric sites metalloallostery. Despite extensive studies, until now, it has not been fully understood how silver inhibits its authentic protein targets, particularly at the atomic level, largely owing to the lack of knowledge on the authentic protein targets of silver as well as the limited structures available. Herein we show that malate dehydrogenase (MDH) serves as a vital target of antimicrobial Ag against . Ag binds MDH at multiple sites and inhibits its activity a non-competitive mechanism. Importantly, we successfully captured the Ag-mediated "open-to-closed" conformational change of the active-site of MDH by X-ray crystallography. Combined with the enzyme kinetics and mutagenesis data, we unambiguously unveil that the allosteric inhibition of MDH by Ag is attributable to its binding to the cysteine residue (Cys251), consequently leading to the closure of the active-site loop of MDH, which disrupts the substrate and coenzyme binding, and ultimately inhibiting the activity of MDH. Our studies provide the first structural glimpse of an unprecedented allosteric inhibition of authentic target enzymes by silver. These findings not only enhance our understanding of the mechanism underlying silver inhibition of its protein targets at the atomic level, but also offer a novel allosteric targeting site in MDH for the design of new antibiotics.

PubMed: 41104151
DOI: 10.1039/d5sc05183e

Experimental method

X-RAY DIFFRACTION (1.56 Å)