6CEP

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

Summary for 6CEP

• Entry DOI: 10.2210/pdb6cep/pdb
• Descriptor: L-lactate dehydrogenase B chain, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, OXAMIC ACID, ... (4 entities in total)
• Functional Keywords: ternary complex, heart isoform (h-chain), oxidoreductase
• Biological source: Sus scrofa (Pig)
• Total number of polymer chains: 4
• Total formula weight: 149614.95

Authors

Hoffer, E.D.,Andrews, B.,Dunham, C.M.,Dyer, R.B. (deposition date: 2018-02-12, release date: 2018-06-27, Last modification date: 2023-10-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2 Å)