Binding of steroid substrates reveals the key to the productive transition of the cytochrome P450 OleP,Structure

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Binding of steroid substrates reveals the key to the productive transition of the cytochrome P450 OleP
Structure ( IF 4.4 ) Pub Date : 2024-07-05 , DOI: 10.1016/j.str.2024.06.005
Antonella Costanzo ₁ , Francesca Fata ₂ , Ida Freda ₃ , Maria Laura De Sciscio ₄ , Elena Gugole ₂ , Giovanni Bulfaro ₁ , Matteo Di Renzo ₃ , Luca Barbizzi ₃ , Cécile Exertier ₂ , Giacomo Parisi ₅ , Marco D'Abramo ₄ , Beatrice Vallone ₆ , Carmelinda Savino ₂ , Linda Celeste Montemiglio ₂

Affiliation

OleP is a bacterial cytochrome P450 involved in oleandomycin biosynthesis as it catalyzes regioselective epoxidation on macrolide intermediates. OleP has recently been reported to convert lithocholic acid (LCA) into murideoxycholic acid through a highly regioselective reaction and to unspecifically hydroxylate testosterone (TES). Since LCA and TES mainly differ by the substituent group at the C17, here we used X-ray crystallography, equilibrium binding assays, and molecular dynamics simulations to investigate the molecular basis of the diverse reactivity observed with the two steroids. We found that the differences in the structure of TES and LCA affect the capability of these molecules to directly form hydrogen bonds with N-terminal residues of OleP internal helix I. The establishment of these contacts, by promoting the bending of helix I, fosters an efficient trigger of the open-to-closed structural transition that occurs upon substrate binding to OleP and contributes to the selectivity of the subsequent monooxygenation reaction.

中文翻译：

类固醇底物的结合揭示了细胞色素 P450 OleP 生产转变的关键

OleP 是一种细菌细胞色素 P450，参与竹桃霉素生物合成，因为它催化大环内酯中间体的区域选择性环氧化。最近有报道称，OleP 通过高度区域选择性反应将石胆酸 (LCA) 转化为鼠脱氧胆酸，并非特异性羟化睾酮 (TES)。由于 LCA 和 TES 主要在 C17 处的取代基不同，因此我们使用 X 射线晶体学、平衡结合测定和分子动力学模拟来研究两种类固醇观察到的不同反应性的分子基础。我们发现TES和LCA结构的差异影响了这些分子与OleP内部螺旋I的N端残基直接形成氢键的能力。这些接触的建立，通过促进螺旋I的弯曲，促进了有效触发底物与 OleP 结合时发生的开放到封闭的结构转变，并有助于随后单氧化反应的选择性。

更新日期：2024-07-05

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