6sy1
Crystal structure of the human 2-oxoadipate dehydrogenase DHTKD1 (E1)Crystal structure of the human 2-oxoadipate dehydrogenase DHTKD1 (E1)
Structural highlights
DiseaseDHTK1_HUMAN 2-aminoadipic 2-oxoadipic aciduria;Autosomal dominant Charcot-Marie-Tooth disease type 2Q. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionDHTK1_HUMAN The 2-oxoglutarate dehydrogenase complex catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2). It contains multiple copies of three enzymatic components: 2-oxoglutarate dehydrogenase (E1), dihydrolipoamide succinyltransferase (E2) and lipoamide dehydrogenase (E3) (By similarity). Publication Abstract from PubMedDHTKD1 is a lesser-studied E1 enzyme among the family of 2-oxoacid de-hydrogenases. In complex with E2 (di-hydro-lipo-amide succinyltransferase, DLST) and E3 (dihydrolipo-amide de-hydrogenase, DLD) components, DHTKD1 is involved in lysine and tryptophan catabolism by catalysing the oxidative de-carboxyl-ation of 2-oxoadipate (2OA) in mitochondria. Here, the 1.9 A resolution crystal structure of human DHTKD1 is solved in complex with the thi-amine diphosphate co-factor. The structure reveals how the DHTKD1 active site is modelled upon the well characterized homologue 2-oxoglutarate (2OG) de-hydrogenase but engineered specifically to accommodate its preference for the longer substrate of 2OA over 2OG. A 4.7 A resolution reconstruction of the human DLST catalytic core is also generated by single-particle electron microscopy, revealing a 24-mer cubic scaffold for assembling DHTKD1 and DLD protomers into a megacomplex. It is further demonstrated that missense DHTKD1 variants causing the inborn error of 2-amino-adipic and 2-oxoadipic aciduria impact on the complex formation, either directly by disrupting the interaction with DLST, or indirectly through destabilizing the DHTKD1 protein. This study provides the starting framework for developing DHTKD1 modulators to probe the intricate mitochondrial energy metabolism. Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism.,Bezerra GA, Foster WR, Bailey HJ, Hicks KG, Sauer SW, Dimitrov B, McCorvie TJ, Okun JG, Rutter J, Kolker S, Yue WW IUCrJ. 2020 Jun 10;7(Pt 4):693-706. doi: 10.1107/S205225252000696X. eCollection, 2020 Jul 1. PMID:32695416[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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