The Lysosomal Protein Saposin B Binds Chloroquine
2016
Huta, Brian P. | Mehlenbacher, Matthew R. | Nie, Yan | Lai, Xuelei | Zubieta, Chloe | Bou-Abdallah, Fadi | Doyle, Robert P. | Department of Chemistry [Syracuse, NY] ; Syracuse University | Department of Chemistry [Potsdam] ; State University of New York at Potsdam (SUNY Potsdam) ; State University of New York (SUNY)-State University of New York (SUNY) | European Synchrotron Radiation Facility (ESRF) | Physiologie cellulaire et végétale (LPCV) ; Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG) ; Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA) | - National Institute of General Medical Sciences of the National Institutes of Health Award Number R15GM104879- ATIP-Avenir program (Joint program of the French National Centre for Scientific Research (CNRS) and the French National Institute of Health and Medical Research (INSERM))
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Показать больше [+] Меньше [-]Английский. Chloroquine (CQ) has been widely used in the treatment of malaria since the 1950s, though toxicity and resistance is increasingly limiting its use in the clinic. More recently, CQ is also becoming recognized as an important therapeutic compound for the treatment of autoimmune disorders and has shown activity as an anticancer agent. However, the full extent of CQ pharmacology in humans is still unclear. Herein, we demonstrate that the lysosomal protein saposinB (sapB), critical for select lipid degradation, binds CQ with implications for both CQ function and toxicity. Using isothermal titration calorimetry (ITC) and fluorescence quenching experiments, CQ was shown to bind to the dimeric form of sapB at both pH5.5 and pH7.4 with an average binding affinity of 2.3x10(4)m(-1). X-ray crystallography confirmed this, and the first complete crystal structure of sapB with a bound small molecule (CQ) is reported. The results suggest that sapB might play a role in mitigating CQ-based toxicity and that sapB might itself be overwhelmed by CQ causing impaired lipid degradation.
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