6lpq
Crystal structure of human D-2-hydroxyglutarate dehydrogenase in complex with D-malate (D-MAL)
Structural highlights
DiseaseD2HDH_HUMAN D-2-hydroxyglutaric aciduria. The disease is caused by variants affecting the gene represented in this entry. FunctionD2HDH_HUMAN Catalyzes the oxidation of D-2-hydroxyglutarate to alpha-ketoglutarate.[1] Publication Abstract from PubMedD-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. Structure, substrate specificity, and catalytic mechanism of human D-2-HGDH and insights into pathogenicity of disease-associated mutations.,Yang J, Zhu H, Zhang T, Ding J Cell Discov. 2021 Jan 12;7(1):3. doi: 10.1038/s41421-020-00227-0. PMID:33431826[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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