Introduction to Structural Studies on 2-Oxoglutarate-Dependent Oxygenases and Related Enzymes

Wei Shen Aik, Rasheduzzaman Chowdhury, Ian J. Clifton, Richard J. Hopkinson, Thomas Leissing, Michael A. McDonough, Radosław Nowak, Christopher J. Schofield*, Louise J. Walport

*Corresponding author for this work

Research output: Chapter in book/report/conference proceedingChapterpeer-review

37 Citations (Scopus)

Abstract

Crystallographic studies have revealed that the Fe(ii)- and 2-oxoglutarate (2OG)-dependent oxygenases and structurally related enzymes employ a conserved double-stranded β-helix (DSBH, or jelly-roll) fold to enable oxidation of a wide range of substrates. The N- and C-terminal ends of the DSBH are modified, including by addition of α-helices and β-strands, in a 2OG oxygenase characteristic manner. In some cases inserts occur between the eight β-strands that comprise the core DSBH, most commonly between the fourth and fifth DSBH strands. The DSBH supports residues that enable binding of Fe(ii) and 2OG in a subfamily conserved manner. The single iron ion at the active site is normally relatively deeply bound and ligated by the side chains of three protein residues which form a conserved His-X-Asp/Glu⋯His motif. In some cases, e.g. the 2OG-dependent halogenases, only two iron ligands are present. The sizes of 2OG oxygenases vary considerably, from less than 300 residues, as observed in some small-molecule hydroxylases, to greater than 1000 residues, found in 2OG oxygenases involved in the regulation of protein biosynthesis. In the latter case additional discrete domains are commonly observed, some of which are related to dimerization or to determining substrate selectivity. The structures have revealed conservation in the general mode of 2OG binding, involving bidentate iron coordination and binding of the 2OG C-5 carboxylate by basic (Lys or Arg) and alcohol-bearing residues, but also differences which can be exploited in the generation of highly selective inhibitors. There is considerable variation in the modes of prime substrate binding, which can involve very substantial conformational changes. However, the topology of the DSBH and surrounding elements limits the residues that are involved in substrate binding and, in some cases, dimerization. In this chapter we provide an introduction to the structural biology of 2OG oxygenases and related DSBH enzymes.
Original languageEnglish
Title of host publication2-Oxoglutarate-Dependent Oxygenases
EditorsRobert P. Hausinger, Christopher J. Schofield
Place of PublicationCambridge, UK
PublisherRoyal Society of Chemistry
Chapter2
Pages59-94
Number of pages36
ISBN (Electronic)9781782621959
ISBN (Print)9781849739504
DOIs
Publication statusPublished - 23 Apr 2015

Publication series

NameRSC Metallobiology
Number3
Volume2015-January
ISSN (Print)2045-547X

Scopus Subject Areas

  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

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