Guo Youzhong, Kalathur Ravi C, Liu Qun, Kloss Brian, Bruni Renato, Ginter Christopher, Kloppmann Edda, Rost Burkhard, Hendrickson Wayne A
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
The New York Consortium on Membrane Protein Structure (NYCOMPS), New York Structural Biology Center, 89 Convent Avenue, New York, NY 10027, USA.
Science. 2015 Jan 30;347(6221):551-5. doi: 10.1126/science.aaa1534.
Translocator proteins (TSPOs) bind steroids and porphyrins, and they are implicated in many human diseases, for which they serve as biomarkers and therapeutic targets. TSPOs have tryptophan-rich sequences that are highly conserved from bacteria to mammals. Here we report crystal structures for Bacillus cereus TSPO (BcTSPO) down to 1.7 Å resolution, including a complex with the benzodiazepine-like inhibitor PK11195. We also describe BcTSPO-mediated protoporphyrin IX (PpIX) reactions, including catalytic degradation to a previously undescribed heme derivative. We used structure-inspired mutations to investigate reaction mechanisms, and we showed that TSPOs from Xenopus and man have similar PpIX-directed activities. Although TSPOs have been regarded as transporters, the catalytic activity in PpIX degradation suggests physiological importance for TSPOs in protection against oxidative stress.
转位蛋白（TSPOs）可结合类固醇和卟啉，与多种人类疾病相关，可作为这些疾病的生物标志物和治疗靶点。TSPOs具有富含色氨酸的序列，从细菌到哺乳动物高度保守。本文报道了蜡样芽孢杆菌TSPO（BcTSPO）的晶体结构，分辨率低至1.7 Å，包括与苯二氮䓬类抑制剂PK11195的复合物。我们还描述了BcTSPO介导的原卟啉IX（PpIX）反应，包括催化降解为一种先前未描述的血红素衍生物。我们利用基于结构的突变研究反应机制，结果表明非洲爪蟾和人类的TSPOs具有相似的PpIX导向活性。尽管TSPOs一直被视为转运蛋白，但PpIX降解中的催化活性表明TSPOs在抵抗氧化应激方面具有重要的生理意义。
