Abstract
The zinc-dependent UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) catalyzes the first committed step in the biosynthesis of lipid A, the hydrophobic anchor of lipopolysaccharide (LPS) that constitutes the outermost monolayer of Gram-negative bacteria. As LpxC is crucial for the survival of Gram-negative organisms and has no sequence homology to known mammalian deacetylases or amidases, it is an excellent target for the design of new antibiotics. The solution structure of LpxC from Aquifex aeolicus in complex with a substrate-analog inhibitor, TU-514, reveals a novel α/β fold, a unique zinc-binding motif and a hydrophobic passage that captures the acyl chain of the inhibitor. On the basis of biochemical and structural studies, we propose a catalytic mechanism for LpxC, suggest a model for substrate binding and provide evidence that mobility and dynamics in structural motifs close to the active site have key roles in the capture of the substrate.
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Acknowledgements
We thank J. Rudolph for helpful and stimulating discussions. This work was supported by grants from the US National Institutes of Health (NIH) and National Institute of General Medical Sciences (to C.R.H.R.), the NIH and National Institute of Allergy and Infectious Diseases (to P.Z.), the Natural Science and Engineering Research Council of Canada (to O.H.) and the Whitehead Institute (to P.Z.). X.L. is the recipient of a graduate scholarship in carbohydrate chemistry from the Alberta Research Council.
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Coggins, B., Li, X., McClerren, A. et al. Structure of the LpxC deacetylase with a bound substrate-analog inhibitor. Nat Struct Mol Biol 10, 645–651 (2003). https://doi.org/10.1038/nsb948
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DOI: https://doi.org/10.1038/nsb948
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