6K12

Babesia microti lactate dehydrogenase apo form (BmLDH)

Summary for 6K12

• Entry DOI: 10.2210/pdb6k12/pdb
• Descriptor: L-lactate dehydrogenase (1 entity in total)
• Functional Keywords: lactate dehydrogenase, inhibitor, oxidoreductase
• Biological source: Babesia microti (strain RI)
• Total number of polymer chains: 6
• Total formula weight: 219860.69

Authors

Long, Y. (deposition date: 2019-05-09, release date: 2019-10-16, Last modification date: 2023-11-22)

Primary citation

Yu, L.,Shen, Z.,Liu, Q.,Zhan, X.,Luo, X.,An, X.,Sun, Y.,Li, M.,Wang, S.,Nie, Z.,Ao, Y.,Zhao, Y.,Peng, G.,Mamoun, C.B.,He, L.,Zhao, J.
Crystal structures ofBabesia microtilactate dehydrogenase BmLDH reveal a critical role for Arg99 in catalysis.
Faseb J., 33:13669-13682, 2019

PubMed Abstract: The tick- and transfusion-transmitted human pathogen infects host erythrocytes to cause the pathologic symptoms associated with human babesiosis, an emerging disease with worldwide distribution and potentially fatal clinical outcome. Drugs currently recommended for the treatment of babesiosis are associated with a high failure rate and significant adverse events, highlighting the urgent need for more-effective and safer babesiosis therapies. Unlike other apicomplexan parasites, lacks a canonical lactate dehydrogenase (LDH) but instead expresses a unique enzyme, LDH (BmLDH), acquired through evolution by horizontal transfer from a mammalian host. Here, we report the crystal structures of BmLDH in apo state and ternary complex (enzyme-NADH-oxamate) solved at 2.79 and 1.89 Å. Analysis of these structures reveals that upon binding to the coenzyme and substrate, the active pocket of BmLDH undergoes a major conformational change from an opened and disordered to a closed and stabilized state. Biochemical assays using wild-type and mutant and human LDHs identified Arg99 as a critical residue for the catalytic activity of BmLDH but not its human counterpart. Interestingly, mutation of Arg99 to Ala had no impact on the overall structure and affinity of BmLDH to NADH but dramatically altered the closure of the enzyme's active pocket. Together, these structural and biochemical data highlight significant differences between and human LDH enzymes and suggest that BmLDH could be a suitable target for the development of selective antibabesial inhibitors.-Yu, L., Shen, Z., Liu, Q., Zhan, X., Luo, X., An, X., Sun, Y., Li, M., Wang, S., Nie, Z., Ao, Y., Zhao, Y., Peng, G., Ben Mamoun, C., He, L., Zhao, J. Crystal structures of lactate dehydrogenase BmLDH reveal a critical role for Arg99 in catalysis.

PubMed: 31585506
DOI: 10.1096/fj.201901259R

Experimental method

X-RAY DIFFRACTION (2.794 Å)