4L4S

Structural characterisation of the NADH binary complex of human lactate dehydrogenase M isozyme

Summary for 4L4S

• Entry DOI: 10.2210/pdb4l4s/pdb
• Related: 4L4R
• Descriptor: L-lactate dehydrogenase A chain, 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE (3 entities in total)
• Functional Keywords: glycolysis, anaerobic respiration, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P00338
• Total number of polymer chains: 2
• Total formula weight: 76680.11

Authors

Dempster, S.,Harper, S.,Moses, J.E.,Dreveny, I. (deposition date: 2013-06-09, release date: 2014-04-30, Last modification date: 2024-02-28)

Primary citation

Dempster, S.,Harper, S.,Moses, J.E.,Dreveny, I.
Structural characterization of the apo form and NADH binary complex of human lactate dehydrogenase.
Acta Crystallogr.,Sect.D, 70:1484-1490, 2014

PubMed Abstract: 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 Å 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.

PubMed: 24816116
DOI: 10.1107/S1399004714005422

Experimental method

X-RAY DIFFRACTION (2.9 Å)