4klv Citations

Structural, functional and inhibition studies of a GNAT superfamily protein PA4794: a new C-terminal lysine protein acetyltransferase from Pseudomonas aeruginosa.

J. Biol. Chem. (2013)
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Cited: 9 times
EuropePMC logo PMID: 24003232


The Gcn5-related N-acetyltransferase (GNAT) superfamily is a large group of evolutionarily related acetyltransferases, with multiple paralogs in organisms from all kingdoms of life. The functionally characterized GNATs have been shown to catalyze the transfer of an acetyl group from acetyl-coenzyme A (AcCoA) to the amine of a wide range of substrates, including small molecules and proteins. GNATs are prevalent and implicated in a myriad of aspects of eukaryotic and prokaryotic physiology, but functions of many GNATs remain unknown. In this work, we used a multi-pronged approach of X-ray crystallography and biochemical characterization to elucidate the sequence-structure-function relationship of the GNAT superfamily member PA4794 from Pseudomonas aeruginosa. We determined that PA4794 acetylates the Nε amine of a C-terminal lysine residue of a peptide, suggesting it is a protein acetyltransferase specific for a C-terminal lysine of a substrate protein or proteins. Further, we identified a number of molecules, including cephalosporin antibiotics, that are inhibitors of PA4794 and bind in its substrate-binding site. Often, these molecules mimic the conformation of the acetylated peptide product. We have determined structures of PA4794 in the apo-form, in complexes with AcCoA, CoA, several antibiotics and other small molecules, and a ternary complex with the products of the reaction: CoA and acetylated peptide. Also, we analyzed PA4794 mutants to identify residues important for substrate binding and catalysis.

Reviews citing this publication (3)

  1. Bacterial GCN5-Related N-Acetyltransferases: From Resistance to Regulation. Favrot L, Blanchard JS, Vergnolle O. Biochemistry 55 989-1002 (2016)
  2. Structure and Functional Diversity of GCN5-Related N-Acetyltransferases (GNAT). Salah Ud-Din AI, Tikhomirova A, Roujeinikova A. Int J Mol Sci 17 (2016)
  3. The future of crystallography in drug discovery. Zheng H, Hou J, Zimmerman MD, Wlodawer A, Minor W. Expert Opin Drug Discov 9 125-137 (2014)

Articles citing this publication (6)

  1. Allostery and conformational dynamics in cAMP-binding acyltransferases. Podobnik M, Siddiqui N, Rebolj K, Nambi S, Merzel F, Visweswariah SS. J. Biol. Chem. 289 16588-16600 (2014)
  2. Double trouble-Buffer selection and His-tag presence may be responsible for nonreproducibility of biomedical experiments. Majorek KA, Kuhn ML, Chruszcz M, Anderson WF, Minor W. Protein Sci. 23 1359-1368 (2014)
  3. Proteomic profiling of lysine acetylation in Pseudomonas aeruginosa reveals the diversity of acetylated proteins. Ouidir T, Cosette P, Jouenne T, Hardouin J. Proteomics 15 2152-2157 (2015)
  4. Crystal structure of Helicobacter pylori pseudaminic acid biosynthesis N-acetyltransferase PseH: implications for substrate specificity and catalysis. Ud-Din AI, Liu YC, Roujeinikova A. PLoS ONE 10 e0115634 (2015)
  5. Protein purification and crystallization artifacts: The tale usually not told. Niedzialkowska E, Gasiorowska O, Handing KB, Majorek KA, Porebski PJ, Shabalin IG, Zasadzinska E, Cymborowski M, Minor W. Protein Sci. 25 720-733 (2016)
  6. The role of lysine(100) in the binding of acetylcoenzyme A to human arylamine N-acetyltransferase 1: implications for other acetyltransferases. Minchin RF, Butcher NJ. Biochem. Pharmacol. 94 195-202 (2015)