6CEP

Sus scrofa heart L-lactate dehydrogenase ternary complex with NADH and oxamate

6CEP の概要

• エントリーDOI: 10.2210/pdb6cep/pdb
• 分子名称: L-lactate dehydrogenase B chain, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, OXAMIC ACID, ... (4 entities in total)
• 機能のキーワード: ternary complex, heart isoform (h-chain), oxidoreductase
• 由来する生物種: Sus scrofa (Pig)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 149614.95

構造登録者

Hoffer, E.D.,Andrews, B.,Dunham, C.M.,Dyer, R.B. (登録日: 2018-02-12, 公開日: 2018-06-27, 最終更新日: 2023-10-04)

主引用文献

Andrews, B.A.,Dyer, R.B.
Small molecule cores demonstrate non-competitive inhibition of lactate dehydrogenase.
Medchemcomm, 9:1369-1376, 2018

PubMed Abstract: Lactate dehydrogenase (LDH) has recently garnered attention as an attractive target for cancer therapies, owing to the enzyme's critical role in cellular metabolism. Current inhibition strategies, employing substrate or cofactor analogues, are insufficiently specific for use as pharmaceutical agents. The possibility of allosteric inhibition of LDH was postulated on the basis of theoretical docking studies of a small molecule inhibitor to LDH. The present study examined structural analogues of this proposed inhibitor to gauge its potency and attempt to elucidate the molecular mechanism of action. These analogues display encouraging inhibition of porcine heart LDH, including micromolar values and a maximum inhibition of up to 50% in the steady state. Furthermore, Michaelis-Menten kinetics and fluorescence data both suggest the simple, acetaminophen derivatives are non-competitive in binding to the enzyme. Kinetic comparisons of a panel of increasingly decorated structural analogues imply that the binding is specific, and the small molecule core provides a privileged scaffold for further pharmaceutical development of a novel, allosteric drug.

PubMed: 30151092
DOI: 10.1039/c8md00309b

実験手法

X-RAY DIFFRACTION (2 Å)