Shah Manish B, Liu Jingbao, Zhang Qinghai, Stout C David, Halpert James R
School of Pharmacy, University of Connecticut , Storrs, Connecticut, United States.
The Department of Integrative Structural and Computational Biology, The Scripps Research Institute , La Jolla, California, United States.
ACS Chem Biol. 2017 May 19;12(5):1204-1210. doi: 10.1021/acschembio.7b00056. Epub 2017 Apr 6.
Numerous cytochrome P450 (CYP) 2B6 substrates including drugs and environmental chemicals are halogenated. To assess the role of halogen-π bonds in substrate selectivity and orientation in the active site, structures of four CYP2B6 monoterpenoid complexes were solved by X-ray crystallography. Bornyl bromide exhibited dual orientations in the active site with the predominant orientation revealing a bromine-π bond with the Phe108 side chain. Bornane demonstrated two orientations with equal occupancy; in both, the C2 atom that bears the bromine in bornyl bromide was displaced by more than 2.5 Å compared with the latter complex. The bromine in myrtenyl bromide π-bonded with Phe297 in CYP2B6, whereas the two major orientations in the active site mutant I114V exhibited bromine-π interactions with two additional residues, Phe108 and Phe115. Analysis of existing structures suggests that halogen-π interactions may be unique to the CYP2B enzymes within CYP family 2 but are also important for CYP3A enzymes.
许多细胞色素P450（CYP）2B6底物，包括药物和环境化学物质，都是卤代的。为了评估卤素-π键在活性位点底物选择性和取向中的作用，通过X射线晶体学解析了四种CYP2B6单萜类化合物复合物的结构。冰片基溴在活性位点呈现出两种取向，主要取向显示出溴与苯丙氨酸108侧链形成的溴-π键。莰烷呈现出两种占有率相等的取向；在这两种取向中，与后一种复合物相比，冰片基溴中带有溴的C2原子位移超过2.5 Å。桃金娘烯基溴中的溴与CYP2B6中的苯丙氨酸297形成π键，而活性位点突变体I114V中的两种主要取向显示溴与另外两个残基苯丙氨酸108和苯丙氨酸115形成溴-π相互作用。对现有结构的分析表明，卤素-π相互作用可能是细胞色素P450家族2中CYP2B酶所特有的，但对CYP3A酶也很重要。
