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Article Dans Une Revue ChemMedChem Année : 2016

The Lysosomal Protein Saposin B Binds Chloroquine

Résumé

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.

Dates et versions

hal-01272103 , version 1 (10-02-2016)

Identifiants

Citer

Brian P. Huta, Matthew R. Mehlenbacher, Yan Nie, Xuelei Lai, Chloe Zubieta, et al.. The Lysosomal Protein Saposin B Binds Chloroquine. ChemMedChem, 2016, 11 (3), pp.277-282. ⟨10.1002/cmdc.201500494⟩. ⟨hal-01272103⟩
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