4QT0

Crystal structure of human muscle L-lactate dehydrogenase in complex with inhibitor 1, 3-{[3-CARBAMOYL-7-(2,4-DIMETHOXYPYRIMIDIN-5-YL)QUINOLIN-4-YL]AMINO}BENZOIC ACID

Summary for 4QT0

• Entry DOI: 10.2210/pdb4qt0/pdb
• Related: 4OJN 4OKN 4QSM
• Descriptor: L-lactate dehydrogenase A chain, 3-{[3-carbamoyl-7-(2,4-dimethoxypyrimidin-5-yl)quinolin-4-yl]amino}benzoic acid (3 entities in total)
• Functional Keywords: rossmann fold, tetramer, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P00338
• Total number of polymer chains: 8
• Total formula weight: 303022.17

Authors

Kolappan, S.,Craig, L. (deposition date: 2014-07-06, release date: 2014-12-03, Last modification date: 2024-02-28)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3.2 Å)