4OJN

Crystal structure of human muscle L-lactate dehydrogenase

4OJN の概要

• エントリーDOI: 10.2210/pdb4ojn/pdb
• 関連するPDBエントリー: 4OKN
• 分子名称: L-lactate dehydrogenase A chain, PENTAETHYLENE GLYCOL, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: rossmann fold, nadh/nad+ cofactor, oxidoreductase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P00338
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 301641.26

構造登録者

Kolappan, S.,Craig, L. (登録日: 2014-01-21, 公開日: 2014-12-03, 最終更新日: 2024-02-28)

主引用文献

Kolappan, S.,Shen, D.L.,Mosi, R.,Sun, J.,McEachern, E.J.,Vocadlo, D.J.,Craig, L.
Structures of lactate dehydrogenase A (LDHA) in apo, ternary and inhibitor-bound forms.
Acta Crystallogr.,Sect.D, 71:185-195, 2015

PubMed Abstract: Lactate dehydrogenase (LDH) is an essential metabolic enzyme that catalyzes the interconversion of pyruvate and lactate using NADH/NAD(+) as a co-substrate. Many cancer cells exhibit a glycolytic phenotype known as the Warburg effect, in which elevated LDH levels enhance the conversion of glucose to lactate, making LDH an attractive therapeutic target for oncology. Two known inhibitors of the human muscle LDH isoform, LDHA, designated 1 and 2, were selected, and their IC50 values were determined to be 14.4 ± 3.77 and 2.20 ± 0.15 µM, respectively. The X-ray crystal structures of LDHA in complex with each inhibitor were determined; both inhibitors bind to a site overlapping with the NADH-binding site. Further, an apo LDHA crystal structure solved in a new space group is reported, as well as a complex with both NADH and the substrate analogue oxalate bound in seven of the eight molecules and an oxalate only bound in the eighth molecule in the asymmetric unit. In this latter structure, a kanamycin molecule is located in the inhibitor-binding site, thereby blocking NADH binding. These structures provide insights into LDHA enzyme mechanism and inhibition and a framework for structure-assisted drug design that may contribute to new cancer therapies.

PubMed: 25664730
DOI: 10.1107/S1399004714024791

実験手法

X-RAY DIFFRACTION (2.4 Å)