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Structure of a specific alcohol-binding site defined by the odorant binding protein LUSH from Drosophila melanogaster

Nature Structural & Molecular Biology volume 10, pages 694–700 (2003)Cite this article

An Addendum to this article was published on 01 January 2004

Abstract

We have solved the high-resolution crystal structures of the Drosophila melanogaster alcohol-binding protein LUSH in complex with a series of short-chain n-alcohols. LUSH is the first known nonenzyme protein with a defined in vivo alcohol-binding function. The structure of LUSH reveals a set of molecular interactions that define a specific alcohol-binding site. A group of amino acids, Thr57, Ser52 and Thr48, form a network of concerted hydrogen bonds between the protein and the alcohol that provides a structural motif to increase alcohol-binding affinity at this site. This motif seems to be conserved in a number of mammalian ligand-gated ion channels that are directly implicated in the pharmacological effects of alcohol. Further, these sequences are found in regions of ion channels that are known to confer alcohol sensitivity. We suggest that the alcohol-binding site in LUSH represents a general model for alcohol-binding sites in proteins.

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Figure 1: Ribbon diagrams of LUSH and PBP.
Figure 2: Structure of LUSH alcohol-binding pocket.
Figure 3: 1H-15N HSQC spectra of LUSH recorded with and without alcohol.
Figure 4: Comparison of the alcohol-binding site in LUSH with regions of alcohol-sensitive ion channels.

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Protein Data Bank

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Acknowledgements

We thank M. Churchill for invaluable advice on crystallography studies and H. Robinson for MAD data collection at Brookhaven National Laboratory. X-ray crystallography facilities and NMR spectrometers were purchased with funds provided by Howard Hughes Medical Institute and their operation is supported by the University of Colorado Cancer Center Core Grant. S.W.K. is supported by an American Heart Association Predoctoral Fellowship. This work is supported by an American Heart Association Development Grant and a grant from the US National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism to D.N.M.J.

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Authors and Affiliations

  1. Department of Pharmacology, University of Colorado Health Sciences Center, M/S C236, 4200 East Ninth Avenue, Denver, 80262, Colorado, USA

    Schoen W Kruse & David N M Jones

  2. Departments of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, M/S C236, 4200 East Ninth Avenue, Denver, 80262, Colorado, USA

    Rui Zhao

  3. Department of Pharmacology and Center for Basic Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390, Texas, USA

    Dean P Smith

  4. Program in Biomolecular Structure, University of Colorado Health Sciences Center, M/S C236, 4200 East Ninth Avenue, Denver, 80262, Colorado, USA

    David N M Jones

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Correspondence to David N M Jones.

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Kruse, S., Zhao, R., Smith, D. et al. Structure of a specific alcohol-binding site defined by the odorant binding protein LUSH from Drosophila melanogaster. Nat Struct Mol Biol 10, 694–700 (2003). https://doi.org/10.1038/nsb960

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