Structural highlights
Publication Abstract from PubMedTwo of nature's recurring binding motifs in metalloproteins are the CxxxCxxC motif in radical SAM enzymes and the 2-His-1-carboxylate motif found both in zincins and alpha-ketoglutarate and non-haem iron enzymes. Here we show the confluence of these two domains in a single post-translational modifying enzyme containing an N-terminal radical S-adenosylmethionine domain fused to a C-terminal 2-His-1-carboxylate (HExxH) domain. The radical SAM domain catalyses three-residue cyclophane formation and is the signature modification of triceptides, a class of ribosomally synthesized and post-translationally modified peptides. The HExxH domain is a defining feature of zinc metalloproteases. Yet the HExxH motif-containing domain studied here catalyses beta-hydroxylation and is an alpha-ketoglutarate non-haem iron enzyme. We determined the crystal structure for this HExxH protein at 2.8 A, unveiling a distinct structural fold, thus expanding the family of alpha-ketoglutarate non-haem iron enzymes with a class that we propose to name alphaKG-HExxH. alphaKG-HExxH proteins represent a unique family of ribosomally synthesized and post-translationally modified peptide modifying enzymes that can furnish opportunities for genome mining, synthetic biology and enzymology. Fused radical SAM and alphaKG-HExxH domain proteins contain a distinct structural fold and catalyse cyclophane formation and beta-hydroxylation.,Morishita Y, Ma S, De La Mora E, Li H, Chen H, Ji X, Usclat A, Amara P, Sugiyama R, Tooh YW, Gunawan G, Perard J, Nicolet Y, Zhang Q, Morinaka BI Nat Chem. 2024 Sep 18. doi: 10.1038/s41557-024-01596-9. PMID:39294420[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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