6u3j

Structure of the 2-oxoadipate dehydrogenase DHTKD1

spinqualitylabelsall models 6u3j, resolution 2.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6u3j is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.25Å Ligands: MG, MLZ, TPP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease DHTK1_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. Function DHTK1_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 PubMed DHTKD1 is the E1 component of the 2-oxoadipate dehydrogenase complex, which is an enzyme involved in the catabolism of (hydroxy-)lysine and tryptophan. Mutations in DHTKD1 have been associated with 2-aminoadipic and 2-oxoadipic aciduria, Charcot-Marie-Tooth disease type 2Q and eosinophilic esophagitis, but the pathophysiology of these clinically distinct disorders remains elusive. Here, we report the identification of adipoylphosphonic acid and tenatoprazole as DHTKD1 inhibitors using targeted and high throughput screening, respectively. We furthermore elucidate the DHTKD1 crystal structure with thiamin diphosphate bound at 2.25 A. We also report the impact of 10 disease-associated missense mutations on DHTKD1. Whereas the majority of the DHTKD1 variants displayed impaired folding or reduced thermal stability in combination with absent or reduced enzyme activity, three variants showed no abnormalities. Our work provides chemical and structural tools for further understanding of the function of DHTKD1 and its role in several human pathologies. Inhibition and Crystal Structure of the Human DHTKD1-Thiamin Diphosphate Complex.,Leandro J, Khamrui S, Wang H, Suebsuwong C, Nemeria NS, Huynh K, Moustakim M, Secor C, Wang M, Dodatko T, Stauffer B, Wilson CG, Yu C, Arkin MR, Jordan F, Sanchez R, DeVita RJ, Lazarus MB, Houten SM ACS Chem Biol. 2020 Jul 9. doi: 10.1021/acschembio.0c00114. PMID:32633484 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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