CW EPR parameters reveal cytochrome P450 ligand binding modes.
CW EPR parameters reveal cytochrome P450 ligand binding modes.
复制标题
DOI：
10.1016/j.jinorgbio.2018.02.021
复制
发表时间：
2018-06
影响因子：
3.9
通讯作者：
Bowman MK
中科院分区：
文献类型：
--
作者：
Lockart MM;Rodriguez CA;Atkins WM;Bowman MK
细胞色素P450单加氧酶（CYP）利用血红素辅因子催化氧化反应。它们在许多类药物的代谢中起关键作用，是药物开发的有吸引力的靶点，并介导几种突出的药物相互作用。许多底物和抑制剂改变自旋状态的铁血红素取代血红素的轴向水配体在休息酶产生一个五配位铁（I型复合物），或他们取代轴向水产生氮连接的六配位铁（II型复合物），这是传统上分配的紫外-可见光谱。然而，晶体结构和最近的脉冲电子顺磁共振（EPR）的研究发现了一些情况下，分子氢键的轴向水。水桥药物-H2O-血红素具有与II型复合物相似的紫外-可见光谱，但更接近于旧文献中描述的“反向I型”复合物。在这里，脉冲和连续波（CW）EPR表明，水桥复合物是非常常见的一系列含氮药物或药物片段，结合到CYP 3A 4或CYP 2C 9。主成分分析揭示了一个独特的聚类CW EPR光谱参数的水桥配合物。CW EPR揭示了异质混合物的配位状态，包括多个II型复合物和水桥血红素复合物。这些结果表明，水桥复合物在非线性结构数据库中代表性不足，并且可以具有与其他连接模式相似的能量。数据表明，水桥结合模式可以识别和区分直接协调的结合CW EPR。
Cytochrome P450 monoxygenses (CYPs) utilize heme cofactors to catalyze oxidation reactions. They play a critical role in metabolism of many classes of drugs, are an attractive target for drug development, and mediate several prominent drug interactions. Many substrates and inhibitors alter the spin state of the ferric heme by displacing the heme’s axial water ligand in the resting enzyme to yield a pentacoordinate iron (type I complex), or they replace the axial water to yield a nitrogen-ligated hexacoordinate iron (type II complex), which are traditionally assigned by UV-vis spectroscopy. However, crystal structures and recent pulsed electron paramagnetic resonance (EPR) studies find a few cases where molecules hydrogen bond to the axial water. The water-bridged drug-H2O-heme has UV-vis spectra similar to type II complexes, but are closer to “reverse type I” complexes described in older liteature. Here, pulsed and continuous wave (CW) EPR demonstrate that water-bridged complexes are remarkably common among a range of nitrogenous drugs or drug fragments that bind to CYP3A4 or CYP2C9. Principal component analysis reveals a distinct clustering of CW EPR spectral parameters for water-bridged complexes. CW EPR reveals heterogeneous mixtures of ligated states, including multiple type II complexes and water-bridged heme complexes. These results suggest that water-bridged complexes are under-represented in CYP structural databases and can have energies similar to other ligation modes. The data indicates that water-bridged binding modes can be identified and distinguished from directly-coordinated binding by CW EPR.
登录
查看更多内容
影响因子：
7.3
作者：
Peng, Chi-Chi;Cape, Jonathan L.;Jones, Jeffrey P.
通讯作者：
Jones, Jeffrey P.
无底物细胞色素P450中轴向水结扎的强度取决于同工型。
影响因子：
2.9
作者：
Conner, Kip P.;Schimpf, Alina M.;Cruce, Alex A.;McLean, Kirsty J.;Munro, Andrew W.;Frank, Daniel J.;Krzyaniak, Matthew D.;de Montellano, Paul Ortiz;Bowman, Michael K.;Atkins, William M.
通讯作者：
Atkins, William M.
影响因子：
2.9
作者：
Conner, Kip P.;Cruce, Alex A.;Krzyaniak, Matthew D.;Schimpf, Alina M.;Frank, Daniel J.;de Montellano, Paul Ortiz;Atkins, William M.;Bowman, Michael K.
通讯作者：
Bowman, Michael K.
影响因子：
15
作者：
Fielding AJ;Dornevil K;Ma L;Davis I;Liu A
通讯作者：
Liu A
影响因子：
5.8
作者：
Chiba, M;Tang, CY;Lin, JH
通讯作者：
Lin, JH