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Structure of the essential Haemophilus influenzae UDP-diacylglucosamine pyrophosphohydrolase LpxH in lipid A biosynthesis

Nature Microbiology volume 1, Article number: 16154 (2016) Cite this article

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Abstract

In most Gram-negative pathogens, the hydrolysis of UDP-2,3-diacylglucosamine to generate lipid X in lipid A biosynthesis is catalysed by the membrane-associated enzyme LpxH. We report the crystal structure of LpxH in complex with its product, lipid X, unveiling a unique insertion lid above the conserved architecture of calcineurin-like phosphoesterases. This structure reveals elaborate interactions surrounding lipid X and provides molecular insights into the substrate selectivity, catalysis and inhibition of LpxH.

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Figure 1: Structure of the LpxH–lipid X complex.

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Acknowledgements

This work was supported by grants from the National Institute of General Medical Sciences (NIGMS) (to P.Z., GM115355 and GM51310). Diffraction data were collected at the Northeastern Collaborative Access Team beamlines (24-ID-C and 24-ID-E) funded by NIGMS (GM103403). The Pilatus 6M detector on the 24-ID-C beam line is funded by a NIH-ORIP HEI grant (RR029205). This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory (contract no. DE-AC02-06CH11357). The authors thank Ziqiang Guan for assistance with mass spectrometry analysis and Brian Coggins for critical reading of this manuscript.

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  1. Chul-Jin Lee

    Present address: †Present address: Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.,

Authors and Affiliations

  1. Department of Biochemistry, Duke University Medical Center, Research Drive, Durham, 27710, North Carolina, USA

    Jae Cho, Chul-Jin Lee, Jinshi Zhao, Hayley E. Young & Pei Zhou

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  1. Jae Cho
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  2. Chul-Jin Lee
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Contributions

P.Z. conceptualized the study. J.C. and H.E.Y. purified and crystallized LpxH. J.C., C-J.L. and P.Z. determined the structure. J.Z. carried out mass spectrometry analysis. P.Z. wrote the manuscript with critical inputs from all authors.

Corresponding author

Correspondence to Pei Zhou.

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The authors declare no competing financial interests.

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Supplementary Information

Supplementary Table 1, Supplementary Figures 1-6 (PDF 1588 kb)

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Cho, J., Lee, CJ., Zhao, J. et al. Structure of the essential Haemophilus influenzae UDP-diacylglucosamine pyrophosphohydrolase LpxH in lipid A biosynthesis. Nat Microbiol 1, 16154 (2016). https://doi.org/10.1038/nmicrobiol.2016.154

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