美国圣朱迪儿童研究医院Taosheng Chen团队揭示选择性抑制人细胞色素P450 3A5的结构基础。相关研究成果发表在2021年10月14日出版的《美国化学会杂志》。

人类细胞色素P450（CYP）CYP3A4和CYP3A5酶代谢占据超过一半的上市药物。它们具有高度的结构和底物相似性，通常作为CYP3A4/5一起研究。然而，CYP3A5优先代谢几种临床处方药物，如他克莫司。CYP3A5的遗传多态性使基于种族的他克莫司剂量调整成为减少器官移植后急性排斥反应的必要条件。此外，CYP3A4和CYP3A5的不同组织分布和表达水平可加重治疗期间的毒性。因此，需要CYP3A5的选择性抑制剂来区分CYP3A5和CYP3A4的作用，并作为潜在治疗开发的起点。

为此，研究人员报道了CYP3A5与先前报道的选择性抑制剂丙酸氯倍他索（CBZ）复合物的晶体结构。其是第一个具有I型抑制剂的CYP3A5结构，与先前报道的无底物和II型抑制剂结合结构一起构成了主要的CYP3A5结构形式。在结构导向突变分析的支持下，CYP3A5–CBZ结构表明，CYP3A5中F–F′环的独特构象使CBZ能够选择性结合CYP3A5。几个极性相互作用，包括氢键，稳定了CBZ的位置，并与这种独特的F–F′环构象相互作用。此外，使用CBZ类似物的功能和生物物理分析强调了血红素相邻部分对选择性CYP3A5抑制的重要性。该研究发现可用于指导更有效和选择性CYP3A5抑制剂的进一步开发。

附：英文原文

Title: Unraveling the Structural Basis of Selective Inhibition of Human Cytochrome P450 3A5

Author: Jingheng Wang, Cameron D. Buchman, Jayaraman Seetharaman, Darcie J. Miller, Andrew D. Huber, Jing Wu, Sergio C. Chai, Efren Garcia-Maldonado, William C. Wright, Jude Chenge, Taosheng Chen

Issue&Volume: October 14, 2021

Abstract: The human cytochrome P450 (CYP) CYP3A4 and CYP3A5 enzymes metabolize more than one-half of marketed drugs. They share high structural and substrate similarity and are often studied together as CYP3A4/5. However, CYP3A5 preferentially metabolizes several clinically prescribed drugs, such as tacrolimus. Genetic polymorphism in CYP3A5 makes race-based dosing adjustment of tacrolimus necessary to minimize acute rejection after organ transplantation. Moreover, the differential tissue distribution and expression levels of CYP3A4 and CYP3A5 can aggravate toxicity during treatment. Therefore, selective inhibitors of CYP3A5 are needed to distinguish the role of CYP3A5 from that of CYP3A4 and serve as starting points for potential therapeutic development. To this end, we report the crystal structure of CYP3A5 in complex with a previously reported selective inhibitor, clobetasol propionate (CBZ). This is the first CYP3A5 structure with a type I inhibitor, which along with the previously reported substrate-free and type II inhibitor-bound structures, constitute the main CYP3A5 structural modalities. Supported by structure-guided mutagenesis analyses, the CYP3A5–CBZ structure showed that a unique conformation of the F–F′ loop in CYP3A5 enables selective binding of CBZ to CYP3A5. Several polar interactions, including hydrogen bonds, stabilize the position of CBZ to interact with this unique F–F′ loop conformation. In addition, functional and biophysical assays using CBZ analogs highlight the importance of heme-adjacent moieties for selective CYP3A5 inhibition. Our findings can be used to guide further development of more potent and selective CYP3A5 inhibitors.

DOI: 10.1021/jacs.1c07066

Source: https://pubs.acs.org/doi/10.1021/jacs.1c07066