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Crystal structures of Saccharomyces cerevisiae N-myristoyltransferase with bound myristoyl-CoA and inhibitors reveal the functional roles of the N-terminal region.

Wu J, Tao Y, Zhang M, Howard MH, Gutteridge S, Ding J
J Biol Chem 282 22185-94 (2007)
Related entries: 2p6e, 2p6g

Cited: 23 times
EuropePMC logo PMID: 17513302

Abstract

Protein N-myristoylation catalyzed by myristoyl-CoA:protein N-myristoyltransferase (NMT) plays an important role in a variety of critical cellular processes and thus is an attractive target for development of antifungal drugs. We report here three crystal structures of Saccharomyces cerevisiae NMT: in binary complex with myristoyl-CoA (MYA) alone and in two ternary complexes involving MYA and two different non-peptidic inhibitors. In all three structures, the majority of the N-terminal region, absent in all previously reported structures, forms a well defined motif that is located in the vicinity of the peptide substrate-binding site and is involved in the binding of MYA. The Ab loop, which might be involved in substrate recognition, adopts an open conformation, whereas a loop of the N-terminal region (residues 22-24) that covers the top of the substrate-binding site is in the position occupied by the Ab loop when in the closed conformation. Structural comparisons with other NMTs, together with mutagenesis data, suggest that the N-terminal region of NMT plays an important role in the binding of both MYA and peptide substrate, but not in subsequent steps of the catalytic mechanism. The two inhibitors occupy the peptide substrate-binding site and interact with the protein through primarily hydrophobic contacts. Analyses of the inhibitorenzyme interactions provide valuable information for further improvement of antifungal inhibitors targeting NMT.

Reviews - 2p6f mentioned but not cited (1)

  1. Structure and Functional Diversity of GCN5-Related N-Acetyltransferases (GNAT). Salah Ud-Din AI, Tikhomirova A, Roujeinikova A. Int J Mol Sci 17 E1018 (2016)

Articles - 2p6f mentioned but not cited (3)

  1. Discordant and chameleon sequences: their distribution and implications for amyloidogenicity. Gendoo DM, Harrison PM. Protein Sci 20 567-579 (2011)
  2. A target repurposing approach identifies N-myristoyltransferase as a new candidate drug target in filarial nematodes. Galvin BD, Li Z, Villemaine E, Poole CB, Chapman MS, Pollastri MP, Wyatt PG, Carlow CK. PLoS Negl Trop Dis 8 e3145 (2014)
  3. Analyses of the Binding between Water Soluble C60 Derivatives and Potential Drug Targets through a Molecular Docking Approach. Junaid M, Almuqri EA, Liu J, Zhang H. PLoS One 11 e0147761 (2016)


Reviews citing this publication (4)

  1. Global profiling of protein lipidation using chemical proteomic technologies. Tate EW, Kalesh KA, Lanyon-Hogg T, Storck EM, Thinon E. Curr Opin Chem Biol 24 48-57 (2015)
  2. Rhodanine as a scaffold in drug discovery: a critical review of its biological activities and mechanisms of target modulation. Tomašić T, Peterlin Mašič L. Expert Opin Drug Discov 7 549-560 (2012)
  3. N-myristoyltransferase: a prospective drug target for protozoan parasites. Bowyer PW, Tate EW, Leatherbarrow RJ, Holder AA, Smith DF, Brown KA. ChemMedChem 3 402-408 (2008)
  4. The diversity of ACBD proteins - From lipid binding to protein modulators and organelle tethers. Islinger M, Costello JL, Kors S, Soupene E, Levine TP, Kuypers FA, Schrader M. Biochim Biophys Acta Mol Cell Res 1867 118675 (2020)

Articles citing this publication (15)

  1. Protein myristoylation in health and disease. Wright MH, Heal WP, Mann DJ, Tate EW. J Chem Biol 3 19-35 (2010)
  2. High-resolution snapshots of human N-myristoyltransferase in action illuminate a mechanism promoting N-terminal Lys and Gly myristoylation. Dian C, Pérez-Dorado I, Rivière F, Asensio T, Legrand P, Ritzefeld M, Shen M, Cota E, Meinnel T, Tate EW, Giglione C. Nat Commun 11 1132 (2020)
  3. Design and synthesis of inhibitors of Plasmodium falciparum N-myristoyltransferase, a promising target for antimalarial drug discovery. Yu Z, Brannigan JA, Moss DK, Brzozowski AM, Wilkinson AJ, Holder AA, Tate EW, Leatherbarrow RJ. J Med Chem 55 8879-8890 (2012)
  4. High-throughput profiling of N-myristoylation substrate specificity across species including pathogens. Traverso JA, Giglione C, Meinnel T. Proteomics 13 25-36 (2013)
  5. Association of NMT2 with the acyl-CoA carrier ACBD6 protects the N-myristoyltransferase reaction from palmitoyl-CoA. Soupene E, Kao J, Cheng DH, Wang D, Greninger AL, Knudsen GM, DeRisi JL, Kuypers FA. J Lipid Res 57 288-298 (2016)
  6. Homology modeling and molecular dynamics simulation of N-myristoyltransferase from protozoan parasites: active site characterization and insights into rational inhibitor design. Sheng C, Ji H, Miao Z, Che X, Yao J, Wang W, Dong G, Guo W, Lü J, Zhang W. J Comput Aided Mol Des 23 375-389 (2009)
  7. N-terminal region of the catalytic domain of human N-myristoyltransferase 1 acts as an inhibitory module. Kumar S, Sharma RK. PLoS One 10 e0127661 (2015)
  8. Discovery of new antifungal leads via pharmacophore modeling and QSAR analysis of fungal N-myristoyl transferase inhibitors followed by in silico screening. Taha MO, Qandil AM, Al-Haraznah T, Khalaf RA, Zalloum H, Al-Bakri AG. Chem Biol Drug Des 78 391-407 (2011)
  9. Biological Activities Related to Plant Protection and Environmental Effects of Coumarin Derivatives: QSAR and Molecular Docking Studies. Rastija V, Vrandečić K, Ćosić J, Majić I, Šarić GK, Agić D, Karnaš M, Lončarić M, Molnar M. Int J Mol Sci 22 7283 (2021)
  10. Effects of Coumarinyl Schiff Bases against Phytopathogenic Fungi, the Soil-Beneficial Bacteria and Entomopathogenic Nematodes: Deeper Insight into the Mechanism of Action. Rastija V, Vrandečić K, Ćosić J, Šarić GK, Majić I, Agić D, Šubarić D, Karnaš M, Bešlo D, Komar M, Molnar M. Molecules 27 2196 (2022)
  11. N-Myristoyltransferase, a Potential Antifungal Candidate Drug-Target for Aspergillus flavus. Wang Y, Lin R, Liu M, Wang S, Chen H, Zeng W, Nie X, Wang S. Microbiol Spectr 11 e0421222 (2023)
  12. Antifungal Activities of Fluorinated Pyrazole Aldehydes on Phytopathogenic Fungi, and Their Effect on Entomopathogenic Nematodes, and Soil-Beneficial Bacteria. Rastija V, Vrandečić K, Ćosić J, Kanižai Šarić G, Majić I, Agić D, Šubarić D, Karnaš M, Bešlo D, Brahmbhatt H, Komar M. Int J Mol Sci 24 9335 (2023)
  13. Identification of and Structural Insights into Hit Compounds Targeting N-Myristoyltransferase for Cryptosporidium Drug Development. Fenwick MK, Reers AR, Liu Y, Zigweid R, Sankaran B, Shin J, Hulverson MA, Hammerson B, Fernández Álvaro E, Myler PJ, Kaushansky A, Van Voorhis WC, Fan E, Staker BL. ACS Infect Dis 9 1821-1833 (2023)
  14. Structure of N-myristoyltransferase from Aspergillus fumigatus. Shimada T, Suzuki M, Katakura S. Acta Crystallogr D Biol Crystallogr 71 754-761 (2015)
  15. The putative myristoylome of Physcomitrium patens reveals conserved features of myristoylation in basal land plants. Lai L, Ruan J, Xiao C, Yi P. Plant Cell Rep 42 1107-1124 (2023)


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