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The Lysosomal Protein Saposin B Binds Chloroquine
Brian P Huta1, Matthew R Mehlenbacher2, Yan Nie1
1Department of Chemistry, Syracuse University, 111 College Place, Syracuse, NY, 13244, USA.
Chemmedchem
|December 1, 2015
Summary
Saposin B (sapB), a lysosomal protein, binds to chloroquine (CQ), a drug used for malaria and autoimmune diseases. This interaction may affect CQ toxicity and lipid degradation.
Area of Science:
- Biochemistry
- Pharmacology
- Structural Biology
Background:
- Chloroquine (CQ) is a long-standing antimalarial drug also investigated for autoimmune and anticancer therapies.
- CQ's clinical utility is challenged by emerging resistance and toxicity.
- The complete human pharmacology of CQ remains incompletely understood.
Purpose of the Study:
- To investigate the interaction between saposin B (sapB) and chloroquine (CQ).
- To elucidate the structural basis of sapB-CQ binding.
- To explore the implications of this interaction for CQ pharmacology and toxicity.
Main Methods:
- Isothermal titration calorimetry (ITC) and fluorescence quenching assays to determine binding affinity.
- X-ray crystallography to determine the structure of sapB bound to CQ.
- Biochemical assays to assess lipid degradation.
Main Results:
- Saposin B (sapB) binds to the dimeric form of sapB with an average affinity of 2.3×10(4) M⁻¹ at pH 5.5 and 7.4.
- The first crystal structure of sapB complexed with a small molecule (CQ) was determined.
- The binding suggests sapB may modulate CQ toxicity, but high CQ concentrations could impair sapB's lipid degradation function.
Conclusions:
- Saposin B (sapB) directly binds chloroquine (CQ).
- This interaction has potential implications for mitigating CQ toxicity.
- Overwhelmed sapB by CQ may lead to impaired lipid degradation, contributing to CQ's side effects.
Keywords:
chloroquineisothermal titration calorimetrylysosomesmalariaprotein crystal structuressaposin BMore Related Videos
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