6SY1

Crystal structure of the human 2-oxoadipate dehydrogenase DHTKD1 (E1)

Summary for 6SY1

• Entry DOI: 10.2210/pdb6sy1/pdb
• Descriptor: Probable 2-oxoglutarate dehydrogenase E1 component DHKTD1, mitochondrial, THIAMINE DIPHOSPHATE, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: dehydrogenase, transketolase, thiamine pyrophosphate, mg, structural genomics, structural genomics consortium, sgc
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 202775.75

Authors

Bezerra, G.A.,Foster, W.,Shrestha, L.,Pena, I.A.,Coker, J.,Kolker, S.,Nicola, B.B.,von Delft, F.,Edwards, A.,Arrowsmith, C.,Bountra, C.,Yue, W.W.,Structural Genomics Consortium (SGC) (deposition date: 2019-09-26, release date: 2020-06-24, Last modification date: 2024-01-24)

Primary citation

Bezerra, G.A.,Foster, W.R.,Bailey, H.J.,Hicks, K.G.,Sauer, S.W.,Dimitrov, B.,McCorvie, T.J.,Okun, J.G.,Rutter, J.,Kolker, S.,Yue, W.W.
Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism.
Iucrj, 7:693-706, 2020

PubMed Abstract: DHTKD1 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 Å 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 Å 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.

PubMed: 32695416
DOI: 10.1107/S205225252000696X

Experimental method

X-RAY DIFFRACTION (1.87 Å)