title: Energetically unfavorable amide conformations for N6-acetyllysine side chains in refined protein structures.
abstract: The reversible acetylation of lysine to form N6-acetyllysine in the regulation of protein function is a hallmark of epigenetics. Acetylation of the positively charged amino group of the lysine side chain generates a neutral N-alkylacetamide moiety that serves as a molecular "switch" for the modulation of protein function and protein-protein interactions. We now report the analysis of 381 N6-acetyllysine side chain amide conformations as found in 79 protein crystal structures and 11 protein NMR structures deposited in the Protein Data Bank (PDB) of the Research Collaboratory for Structural Bioinformatics. We find that only 74.3% of N6-acetyllysine residues in protein crystal structures and 46.5% in protein NMR structures contain amide groups with energetically preferred trans or generously trans conformations. Surprisingly, 17.6% of N6-acetyllysine residues in protein crystal structures and 5.3% in protein NMR structures contain amide groups with energetically unfavorable cis or generously cis conformations. Even more surprisingly, 8.1% of N6-acetyllysine residues in protein crystal structures and 48.2% in NMR structures contain amide groups with energetically prohibitive twisted conformations that approach the transition state structure for cis-trans isomerization. In contrast, 109 unique N-alkylacetamide groups contained in 84 highly accurate small molecule crystal structures retrieved from the Cambridge Structural Database exclusively adopt energetically preferred trans conformations. Therefore, we conclude that cis and twisted N6-acetyllysine amides in protein structures deposited in the PDB are erroneously modeled due to their energetically unfavorable or prohibitive conformations.
authors: Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, USA.
authors: Alexander
authors: A
authors: Genshaft
authors: Joe-Ann S
authors: JA
authors: Moser
authors: Edward L
authors: EL
authors: D'Antonio
authors: Christine M
authors: CM
authors: Bowman
authors: David W
authors: DW
authors: Christianson
mesh_terms: D000577:Amides / Q000737:chemistry*; D030562:Databases, Protein; D007536:Isomerism; D008239:Lysine / Q000031:analogs & derivatives* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D000577:Amides; D011506:Proteins; C016949:N-epsilon-acetyllysine; D008239:Lysine
references: Cell. 2007 Feb 23;128(4):693-705
references: 17320507
references: Expert Rev Anticancer Ther. 2010 Jun;10(6):935-54
references: 20553216
references: Biochim Biophys Acta. 2009 Jan;1789(1):58-68
references: 18722564
references: Curr Opin Genet Dev. 1999 Apr;9(2):171-4
references: 10322142
references: Biochemistry. 1993 Oct 19;32(41):10944-9
references: 8218160
references: Acta Crystallogr B. 2002 Jun;58(Pt 3 Pt 1):380-8
references: 12037359
references: J Mol Biol. 1971 Jul 14;59(1):169-82
references: 5283751
references: Nature. 2010 Dec 23;468(7327):1067-73
references: 20871596
references: Genes Dev. 2009 Apr 1;23(7):781-3
references: 19339683
references: Acta Crystallogr B. 2002 Jun;58(Pt 3 Pt 1):389-97
references: 12037360
references: Nat Struct Biol. 1998 Aug;5(8):676
references: 9699627
references: J Mol Biol. 1999 Feb 12;286(1):291-304
references: 9931267
references: Biochemistry. 1988 Jun 14;27(12):4538-41
references: 3166998
references: Curr Opin Drug Discov Devel. 2009 Sep;12(5):659-65
references: 19736624
references: Clin Epigenetics. 2011 Aug;2(2):257-77
references: 22704341
references: Proc Natl Acad Sci U S A. 1964 May;51:786-94
references: 14172992
references: Clin Cancer Res. 2004 Jul 15;10(14):4589-96
references: 15269129
references: Nature. 1999 Jun 3;399(6735):491-6
references: 10365964
references: Cell. 2007 Feb 23;128(4):635-8
references: 17320500
references: Annu Rev Biochem. 2011;80:473-99
references: 21529160
references: Biochemistry. 2008 Dec 23;47(51):13554-63
references: 19053282
references: Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):449-53
references: 22198840
references: J Med Chem. 2011 Oct 13;54(19):6612-23
references: 21830831