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Solution structure of the catalytic domain of GCN5 histone acetyltransferase bound to coenzyme A

Nature volume 400, pages 86–89 (1999)Cite this article

Abstract

Gene transcription requires the release of inactive DNA from its packaging of histone proteins. Following the discovery of the first transcription-associated histone acetyltransferase, tetrahymena GCN51, it was shown that yeast GCN5 is recruited to the promoter and causes hyper-acetylation of histones and transcriptional activation of target genes2,3, establishing a direct connection between histone acetylation and transcriptional activation. Many other important transcription regulators have been found to have histone acetyltransferase activity, including TAFii230/250, p300/CBP and its associated factor PCAF4,5,6,7,8,9. Here we present the solution structure of the catalytic domain of tGCN5 (residues 47–210) in complex with coenzyme A. The structure contains two domains; the amino-terminal domain is similar to those of other GCN5-related N-acetyltransferases10,11 but the carboxy-terminal domain is not. Coenzyme A binds in a deep hydrophobic pocket between the two domains. Chemical shift changes upon titration with histone H3 peptides indicate a binding site at the domain boundary opposite to the coenzyme A site. The structural data indicate a single-step acetyl-transfer reaction mechanism catalysed by a hydrogen bond to the backbone amide group of leucine 126 and the side-chain carboxyl group of a conserved acidic residue.

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Figure 1: Sequence and structure of the catalytic domain of tGCN5.
Figure 2: Intermolecular NOEs and hydrogen bonds in the protein–CoA interface.
Figure 3: The binding site for histone H3 peptide.

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Acknowledgements

We thank R. Marmorstein for initiating this work and providing the histone peptides; G. Heffron for help with NMR experiments; V. Ramakrishnan for providing the coordinates of yHat1 before their release by the PDB; and J. Denu for providing a copy of his paper before publication. This project was supported by grants from NSF, NIH, the Harvard Center for Structural Biology and the Giovanni Armenise-Harvard Foundation for Advanced Scientific Research.

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Authors and Affiliations

  1. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Yingxi Lin, C. Mark Fletcher & Gerhard Wagner

  2. MIT/Harvard Center for Magnetic Resonance, Cambridge, 02139, Massachusetts, USA

    Yingxi Lin, C. Mark Fletcher & Gerhard Wagner

  3. Department of Physics, Harvard University, Cambridge, 02138, Massachusetts, USA

    Yingxi Lin

  4. Department of Biochemistry and Molecular Genetics, University of Virginia, 1300 Jefferson Park Avenue, Charlottesville, 22908, Virginia, USA

    Jianxin Zhou & C. David Allis

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  1. Yingxi Lin
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Correspondence to Gerhard Wagner.

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Lin, Y., Fletcher, C., Zhou, J. et al. Solution structure of the catalytic domain of GCN5 histone acetyltransferase bound to coenzyme A. Nature 400, 86–89 (1999). https://doi.org/10.1038/21922

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