8ER0

X-ray crystal structure of Tet(X6) bound to anhydrotetracycline

Summary for 8ER0

• Entry DOI: 10.2210/pdb8er0/pdb
• Descriptor: Flavin-dependent monooxygenase, 5A,6-ANHYDROTETRACYCLINE, FLAVIN-ADENINE DINUCLEOTIDE, ... (4 entities in total)
• Functional Keywords: tetracycline destructase, fad-linked reductases, flavoprotein, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• Biological source: Chryseobacterium oncorhynchi
• Total number of polymer chains: 2
• Total formula weight: 93719.40

Authors

Kumar, H.,Tolia, N.H. (deposition date: 2022-10-11, release date: 2023-04-26, Last modification date: 2023-10-25)

Primary citation

Kumar, H.,Williford, E.E.,Blake, K.S.,Virgin-Downey, B.,Dantas, G.,Wencewicz, T.A.,Tolia, N.H.
Structure of anhydrotetracycline-bound Tet(X6) reveals the mechanism for inhibition of type 1 tetracycline destructases.
Commun Biol, 6:423-423, 2023

PubMed Abstract: Inactivation of tetracycline antibiotics by tetracycline destructases (TDases) remains a clinical and agricultural threat. TDases can be classified as type 1 Tet(X)-like TDases and type 2 soil-derived TDases. Type 1 TDases are widely identified in clinical pathogens. A combination therapy of tetracycline and a TDase inhibitor is much needed to rescue the clinical efficacy of tetracyclines. Anhydrotetracycline is a pan-TDase inhibitor that inhibits both type 1 and type 2 TDases. Here, we present structural, biochemical, and phenotypic evidence that anhydrotetracycline binds in a substrate-like orientation and competitively inhibits the type 1 TDase Tet(X6) to rescue tetracycline antibiotic activity as a sacrificial substrate. Anhydrotetracycline interacting residues of Tet(X6) are conserved within type 1 TDases, indicating a conserved binding mode and mechanism of inhibition. This mode of binding and inhibition is distinct from anhydrotetracycline's inhibition of type 2 TDases. This study forms the framework for development of next-generation therapies to counteract enzymatic tetracycline resistance.

PubMed: 37062778
DOI: 10.1038/s42003-023-04792-4

Experimental method

X-RAY DIFFRACTION (2.2 Å)