Your browser doesn't support javascript.
loading
Structural Basis for Blocking Sugar Uptake into the Malaria Parasite Plasmodium falciparum.
Jiang, Xin; Yuan, Yafei; Huang, Jian; Zhang, Shuo; Luo, Shuchen; Wang, Nan; Pu, Debing; Zhao, Na; Tang, Qingxuan; Hirata, Kunio; Yang, Xikang; Jiao, Yaqing; Sakata-Kato, Tomoyo; Wu, Jia-Wei; Yan, Chuangye; Kato, Nobutaka; Yin, Hang; Yan, Nieng.
Afiliação
  • Jiang X; State Key Laboratory of Membrane Biology, Tsinghua University, Beijing 100084, China; Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China; School of Life Scie
  • Yuan Y; State Key Laboratory of Membrane Biology, Tsinghua University, Beijing 100084, China; Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China; School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • Huang J; Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China; Department of Chemistry, Tsinghua University, Beijing 100084, China.
  • Zhang S; State Key Laboratory of Membrane Biology, Tsinghua University, Beijing 100084, China; Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China; School of Life Scie
  • Luo S; Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China; Department of Chemistry, Tsinghua University, Beijing 100084, China.
  • Wang N; State Key Laboratory of Membrane Biology, Tsinghua University, Beijing 100084, China; Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China; School of Life Scie
  • Pu D; Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China; School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
  • Zhao N; Global Health Drug Discovery Institute, Zhongguancun Dongsheng International Science Park, 1 North Yongtaizhuang Road, Beijing 100192, China.
  • Tang Q; Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China; School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
  • Hirata K; Advanced Photon Technology Division, Research Infrastructure Group, SR Life Science Instrumentation Unit, RIKEN/SPring-8 Center, Hyogo 679-5148, Japan.
  • Yang X; Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China; Department of Chemistry, Tsinghua University, Beijing 100084, China.
  • Jiao Y; Global Health Drug Discovery Institute, Zhongguancun Dongsheng International Science Park, 1 North Yongtaizhuang Road, Beijing 100192, China.
  • Sakata-Kato T; Global Health Drug Discovery Institute, Zhongguancun Dongsheng International Science Park, 1 North Yongtaizhuang Road, Beijing 100192, China.
  • Wu JW; Institute of Molecular Enzymology, Soochow University, Suzhou, Jiangsu 215123, China.
  • Yan C; State Key Laboratory of Membrane Biology, Tsinghua University, Beijing 100084, China; Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China; School of Life Scie
  • Kato N; Global Health Drug Discovery Institute, Zhongguancun Dongsheng International Science Park, 1 North Yongtaizhuang Road, Beijing 100192, China.
  • Yin H; Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China; School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China. Electronic address: yin_ha
  • Yan N; State Key Laboratory of Membrane Biology, Tsinghua University, Beijing 100084, China; Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China; School of Life Scie
Cell ; 183(1): 258-268.e12, 2020 10 01.
Article em En | MEDLINE | ID: mdl-32860739
Plasmodium species, the causative agent of malaria, rely on glucose for energy supply during blood stage. Inhibition of glucose uptake thus represents a potential strategy for the development of antimalarial drugs. Here, we present the crystal structures of PfHT1, the sole hexose transporter in the genome of Plasmodium species, at resolutions of 2.6 Å in complex with D-glucose and 3.7 Å with a moderately selective inhibitor, C3361. Although both structures exhibit occluded conformations, binding of C3361 induces marked rearrangements that result in an additional pocket. This inhibitor-binding-induced pocket presents an opportunity for the rational design of PfHT1-specific inhibitors. Among our designed C3361 derivatives, several exhibited improved inhibition of PfHT1 and cellular potency against P. falciparum, with excellent selectivity to human GLUT1. These findings serve as a proof of concept for the development of the next-generation antimalarial chemotherapeutics by simultaneously targeting the orthosteric and allosteric sites of PfHT1.
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Plasmodium falciparum / Proteínas de Transporte de Monossacarídeos / Proteínas de Protozoários Limite: Animals / Humans Idioma: En Revista: Cell Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Plasmodium falciparum / Proteínas de Transporte de Monossacarídeos / Proteínas de Protozoários Limite: Animals / Humans Idioma: En Revista: Cell Ano de publicação: 2020 Tipo de documento: Article