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Structure of N-myristoyltransferase with bound myristoylCoA and peptide substrate analogs

Nature Structural Biology volume 5, pages 1091–1097 (1998)Cite this article

Abstract

N-myristoyltransferase (Nmt) attaches myristate to the N-terminal glycine of many important eukaryotic and viral proteins. It is a target for anti-fungal and anti-viral therapy. We have determined the structure, to 2.9 Å resolution, of a ternary complex of Saccharomyces cerevisiae Nmt1p with bound myristoylCoA and peptide substrate analogs. The model reveals structural features that define the enzyme's substrate specificities and regulate the ordered binding and release of substrates and products. A novel catalytic mechanism is proposed involving deprotonation of the N-terminal ammonium of a peptide substrate by the enzyme's C-terminal backbone carboxylate.

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Figure 1: Representative regions of electron density.
Figure 2: Nmt1p with bound S-(2-oxo)pentadecyl-CoA and SC-58272.
Figure 3: Contacts between S-(2-oxo)pentadecylCoA and Nmt1p.
Figure 4: Contacts between SC-58272 and Nmt1p.
Figure 5: Active site and proposed reaction mechanism.

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Acknowledgements

We thank B. Devadas, J. Sikorski and C. McWherter (G.D. Searle) for SC-58272, C. Ogata at NSLS, and M. Soltis, and P. Kuhn at SSRL for help with data collection, and J. Kuriyan for helpful comments. This work was supported in part by grants from the NIH and Monsanto.

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Author notes

  1. Rajiv S. Bhatnagar, Klaus Fütterer, Sergey Korolev and Gabriel Waksman: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Rajiv S. Bhatnagar, Thalia A. Farazi, Clare L. Murray, Emily Jackson-Machelski, George W. Gokel & Jeffrey I. Gordon

  2. Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Klaus Fütterer, Sergey Korolev & Gabriel Waksman

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  1. Rajiv S. Bhatnagar
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Correspondence to Gabriel Waksman.

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Bhatnagar, R., Fütterer, K., Farazi, T. et al. Structure of N-myristoyltransferase with bound myristoylCoA and peptide substrate analogs. Nat Struct Mol Biol 5, 1091–1097 (1998). https://doi.org/10.1038/4202

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