Structural characterization of the apo form and NADH binary complex of human lactate dehydrogenase

Dempster, S., Harper, S., Moses, J. E., Dreveny, I. (May 2014) Structural characterization of the apo form and NADH binary complex of human lactate dehydrogenase. Acta Crystallogr D Biol Crystallogr, 70 (Pt 5). pp. 1484-90. ISSN 0907-4449 (Print)0907-4449

DOI: 10.1107/s1399004714005422


Lactate dehydrogenase A (LDH-A) is a key enzyme in anaerobic respiration that is predominantly found in skeletal muscle and catalyses the reversible conversion of pyruvate to lactate in the presence of NADH. LDH-A is overexpressed in many tumours and has therefore emerged as an attractive target for anticancer drug discovery. Crystal structures of human LDH-A in the presence of inhibitors have been described, but currently no structures of the apo or binary NADH-bound forms are available for any mammalian LDH-A. Here, the apo structure of human LDH-A was solved at a resolution of 2.1 � in space group P4122. The active-site loop adopts an open conformation and the packing and crystallization conditions suggest that the crystal form is suitable for soaking experiments. The soaking potential was assessed with the cofactor NADH, which yielded a ligand-bound crystal structure in the absence of any inhibitors. The structures show that NADH binding induces small conformational changes in the active-site loop and an adjacent helix. A comparison with other eukaryotic apo LDH structures reveals the conservation of intra-loop interactions. The structures provide novel insight into cofactor binding and provide the foundation for soaking experiments with fragments and inhibitors.

Item Type: Paper
Uncontrolled Keywords: Catalytic Domain Crystallography, X-Ray Humans Isoenzymes/chemistry/metabolism L-Lactate Dehydrogenase/*chemistry/metabolism Lactate Dehydrogenase 5 Ligands Models, Molecular NAD/chemistry/metabolism Protein Conformation apo structure conformational change glycolysis lactate dehydrogenase ligand soaking
CSHL Authors:
Communities: CSHL labs > Moses lab
Depositing User: Matthew Dunn
Date: May 2014
Date Deposited: 19 Apr 2021 20:00
Last Modified: 19 Apr 2021 20:00
PMCID: PMC4014127
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