6LPP

Crystal structure of human D-2-hydroxyglutarate dehydrogenase in complex with D-2-hydroxyglutarate (D-2-HG)

Summary for 6LPP

• Entry DOI: 10.2210/pdb6lpp/pdb
• Descriptor: D-2-hydroxyglutarate dehydrogenase, mitochondrial, FLAVIN-ADENINE DINUCLEOTIDE, ZINC ION, ... (6 entities in total)
• Functional Keywords: dehydrogenase, flavoprotein, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 107308.55

Authors

Yang, J.,Zhu, H.,Ding, J. (deposition date: 2020-01-12, release date: 2021-01-13, Last modification date: 2023-11-29)

Primary citation

Yang, J.,Zhu, H.,Zhang, T.,Ding, J.
Structure, substrate specificity, and catalytic mechanism of human D-2-HGDH and insights into pathogenicity of disease-associated mutations.
Cell Discov, 7:3-3, 2021

PubMed Abstract: D-2-hydroxyglutarate dehydrogenase (D-2-HGDH) catalyzes the oxidation of D-2-hydroxyglutarate (D-2-HG) into 2-oxoglutarate, and genetic D-2-HGDH deficiency leads to abnormal accumulation of D-2-HG which causes type I D-2-hydroxyglutaric aciduria and is associated with diffuse large B-cell lymphoma. This work reports the crystal structures of human D-2-HGDH in apo form and in complexes with D-2-HG, D-malate, D-lactate, L-2-HG, and 2-oxoglutarate, respectively. D-2-HGDH comprises a FAD-binding domain, a substrate-binding domain, and a small C-terminal domain. The active site is located at the interface of the FAD-binding domain and the substrate-binding domain. The functional roles of the key residues involved in the substrate binding and catalytic reaction and the mutations identified in D-2-HGDH-deficient diseases are analyzed by biochemical studies. The structural and biochemical data together reveal the molecular mechanism of the substrate specificity and catalytic reaction of D-2-HGDH and provide insights into the pathogenicity of the disease-associated mutations.

PubMed: 33431826
DOI: 10.1038/s41421-020-00227-0

Experimental method

X-RAY DIFFRACTION (2.65 Å)