Role of the jelly-roll fold in substrate binding by 2-oxoglutarate oxygenases

• Published in: Current opinion in structural biology 2012-12, Vol.22 (6), p.691-700
• Main Authors: Aik, WeiShen, McDonough, Michael A, Thalhammer, Armin, Chowdhury, Rasheduzzaman, Schofield, Christopher J
• Format: Article
• Language: English
• Subjects: Animals; Enzyme Inhibitors - pharmacology; Humans; Oxygenases - antagonists & inhibitors; Oxygenases - chemistry; Oxygenases - genetics; Oxygenases - metabolism; Protein Binding; Protein Engineering; Protein Structure, Secondary
• ISSN: 0959-440X; 1879-033X
• DOI: 10.1016/j.sbi.2012.10.001

. [Display omitted] ► Structural features of 2OG oxygenases involved in substrate recognition are analyzed. ► Crystallographic studies reveal the versatility of the jelly roll fold in substrate binding. ► Defined structural regions that interact with substrate(s) are biased by fold topology. ► The utility of the enzyme–substrate structures for engineering and selective inhibition are discussed. 2-Oxoglutarate (2OG) and ferrous iron dependent oxygenases catalyze two-electron oxidations of a range of small and large molecule substrates, including proteins/peptides/amino acids, nucleic acids/bases, and lipids, as well as natural products including antibiotics and signaling molecules. 2OG oxygenases employ variations of a core double-stranded β-helix (DSBH; a.k.a. jelly-roll, cupin or jumonji C (JmjC)) fold to enable binding of Fe(II) and 2OG in a subfamily conserved manner. The topology of the DSBH limits regions directly involved in substrate binding: commonly the first, second and eighth strands, loops between the second/third and fourth/fifth DSBH strands, and the N-terminal and C-terminal regions are involved in primary substrate, co-substrate and cofactor binding. Insights into substrate recognition by 2OG oxygenases will help to enable selective inhibition and bioengineering studies.