Human cytochrome P450 3A7 binding four copies of its native substrate dehydroepiandrosterone 3-sulfate.
Human cytochrome P450 3A7 binding four copies of its native substrate dehydroepiandrosterone 3-sulfate.
复制标题
DOI：
10.1016/j.jbc.2023.104993
复制
发表时间：
2023-08
影响因子：
4.8
通讯作者：
Scott, Emily E
中科院分区：
文献类型：
--
作者：
Liu, Jinghan;Kandel, Sylvie E;Lampe, Jed N;Scott, Emily E
人胎儿细胞色素P450 3A 7（CYP 3A 7）参与异生物质代谢和雌三醇生物合成途径。虽然对细胞色素P450 3A 4及其在成人药物代谢中的作用了解很多，但CYP 3A 7在与两类底物的相互作用方面的特征很差。本文中，CYP 3A 7的可结晶突变形式用其主要内源性底物脱氢表雄酮3-硫酸盐（DHEA-S）饱和，产生2.6 μ π ι X射线结构，揭示了同时结合四个DHEA-S拷贝的意外能力。两个DHEA-S分子位于活性位点，一个位于配体进入通道，一个位于通常嵌入膜中的疏水F′-G′表面。虽然DHEA-S结合和代谢均未表现出协同动力学，但目前的结构与CYP 3A酶常见的协同性一致。总体而言，该信息表明CYP 3A 7与甾体底物相互作用的机制很复杂。
Human fetal cytochrome P450 3A7 (CYP3A7) is involved in both xenobiotic metabolism and the estriol biosynthetic pathway. Although much is understood about cytochrome P450 3A4 and its role in adult drug metabolism, CYP3A7 is poorly characterized in terms of its interactions with both categories of substrates. Herein, a crystallizable mutated form of CYP3A7 was saturated with its primary endogenous substrate dehydroepiandrosterone 3-sulfate (DHEA-S) to yield a 2.6 Å X-ray structure revealing the unexpected capacity to simultaneously bind four copies of DHEA-S. Two DHEA-S molecules are located in the active site proper, one in a ligand access channel, and one on the hydrophobic F′–G′ surface normally embedded in the membrane. While neither DHEA-S binding nor metabolism exhibit cooperative kinetics, the current structure is consistent with cooperativity common to CYP3A enzymes. Overall, this information suggests that mechanism(s) of CYP3A7 interactions with steroidal substrates are complex.