4V2O

Structure of saposin B in complex with chloroquine

4V2O の概要

• エントリーDOI: 10.2210/pdb4v2o/pdb
• 分子名称: SAPOSIN-B, N4-(7-CHLORO-QUINOLIN-4-YL)-N1,N1-DIETHYL-PENTANE-1,4-DIAMINE (3 entities in total)
• 機能のキーワード: hydrolase activator, protein-ligand complex
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Lysosome . Prosaposin: Secreted: P07602
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 27932.10

構造登録者

Zubieta, C.,Lai, X.,Doyle, R.P. (登録日: 2014-10-13, 公開日: 2015-12-09, 最終更新日: 2024-10-23)

主引用文献

Huta, B.P.,Mehlenbacher, M.R.,Nie, Y.,Lai, X.,Zubieta, C.,Bou-Abdallah, F.,Doyle, R.P.
The Lysosomal Protein Saposin B Binds Chloroquine.
Chemmedchem, 11:277-, 2016

PubMed Abstract: 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 saposin B (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 pH 5.5 and pH 7.4 with an average binding affinity of 2.3×10(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.

PubMed: 26616259
DOI: 10.1002/CMDC.201500494

実験手法

X-RAY DIFFRACTION (2.13 Å)