6J9D

Babesia microti lactate dehydrogenase R99A (BmLDHR99A)

6J9D の概要

• エントリーDOI: 10.2210/pdb6j9d/pdb
• 分子名称: L-lactate dehydrogenase (1 entity in total)
• 機能のキーワード: bmldh, oxidoreductase
• 由来する生物種: Babesia microti (strain RI)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 67714.51

構造登録者

Yu, L. (登録日: 2019-01-22, 公開日: 2019-10-16, 最終更新日: 2024-03-27)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.904 Å)