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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\u2010effective and safer babesiosis therapies. Unlike other apicomplexan parasites,\n                    <jats:italic>B. microti<\/jats:italic>\n                    lacks a canonical lactate dehydrogenase (LDH) but instead expresses a unique enzyme,\n                    <jats:italic>B. microti<\/jats:italic>\n                    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\u2010NADH\u2010oxamate) solved at 2.79 and 1.89 \u00c5. 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\u2010type and mutant\n                    <jats:italic>B. microti<\/jats:italic>\n                    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\n                    <jats:italic>B. microti<\/jats:italic>\n                    and human LDH enzymes and suggest that BmLDH could be a suitable target for the development of selective antibabesial inhibitors.\u2014Yu, 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., BenMamoun, C., He, L., Zhao, J. Crystal structures of\n                    <jats:italic>Babesia microti<\/jats:italic>\n                    lactate dehydrogenase BmLDH reveal a critical role for Arg99 in catalysis. FASEB J. 33, 13669\u201013682 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201901259r","type":"journal-article","created":{"date-parts":[[2019,10,4]],"date-time":"2019-10-04T20:07:44Z","timestamp":1570219664000},"page":"13669-13682","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Crystal structures of\n                    <i>Babesia microti<\/i>\n                    lactate dehydrogenase BmLDH reveal a critical role for Arg99 in catalysis"],"prefix":"10.1096","volume":"33","author":[{"given":"Long","family":"Yu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University Wuhan China"},{"name":"Key Laboratory of Preventive Veterinary Medicine Wuhan 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Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyin","family":"Luo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University Wuhan China"},{"name":"Key Laboratory of Preventive Veterinary Medicine Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaomeng","family":"An","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University Wuhan China"},{"name":"Key Laboratory of Preventive Veterinary Medicine Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yali","family":"Sun","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University Wuhan China"},{"name":"Key Laboratory of Preventive Veterinary Medicine Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muxiao","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University Wuhan China"},{"name":"Key Laboratory of Preventive Veterinary Medicine Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sen","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University Wuhan China"},{"name":"Key Laboratory of Preventive Veterinary Medicine Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zheng","family":"Nie","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University Wuhan China"},{"name":"Key Laboratory of Preventive Veterinary Medicine Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yangsiqi","family":"Ao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University Wuhan China"},{"name":"Key Laboratory of Preventive Veterinary Medicine Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yangnan","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University Wuhan China"},{"name":"Key Laboratory of Preventive Veterinary Medicine Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guiqing","family":"Peng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University Wuhan China"},{"name":"Key Laboratory 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