Structural basis for the activity and regulation of human α-ketoglutarate dehydrogenase revealed by Cryo-EM

The human mitochondrial alpha-ketoglutarate (alpha-KG) dehydrogenase complex (hKGDHc) is a well-studied macromolecular enzyme that converts alpha-KG to succinyl-CoA and NADH. Abnormalities of the complex lead to several diseases, including neurodegenerative disorders. Despite its importance in human metabolism and diseases, structural information on hKGDHc is not well defined. Here, we report the 2.92 angstrom resolution cryo-electron microscopy (EM) structure of its E1 component 2-oxoglutarate dehydrogenase (OGDH). The density map comprised residues 129-1,023, which is nearly the full length of OGDH. The structure clearly shows the active site and Ca2+ binding site of OGDH. This structural information will improve our understanding of the structure and function of hKGDHc and benefit pharmaceutical and basic science targeting this enzyme complex. (C) 2022 Elsevier Inc. All rights reserved.

Automated summary

This study reports the structural information of the E1 component 2-oxoglutarate dehydrogenase (OGDH) of the human mitochondrial alpha-ketoglutarate dehydrogenase complex (hKGDHc). The cryo-electron microscopy structure reveals the active site and Ca2+ binding site of OGDH. This structural information enhances our understanding of the hKGDHc structure and function and has implications for pharmaceutical and basic science research.