Beautrait Alexandre, Karaboga Arnaud S, Souchet Michel, Maigret Bernard
Nancy-Université, Groupe ORPAILLEUR, UMR CNRS/UHP 7503, LORIA, Campus Scientifique, BP239, 54506 Vandoeuvre-lès-Nancy Cedex, France.
Proteins. 2008 Aug 15;72(3):873-82. doi: 10.1002/prot.21977.
Ligand induced fit phenomenon occurring at the ligand binding domain of the liver X receptor beta (LXRbeta) was investigated by means of molecular dynamics. Reliability of a 4-ns trajectory was tested from two distinct LXRbeta crystal complexes 1PQ6B/GW and 1PQ9B/T09 characterized by an open and a closed state of the pocket, respectively. Crossed complexes 1PQ6B/T09 and 1PQ9B/GW were then submitted to the same molecular dynamic conditions, which were able to recover LXRbeta conformations similar to the original crystallography data. Analysis of "open to closed" and "closed to open" conformational transitions pointed out the dynamic role of critical residues lining the ligand binding pocket involved in the local remodeling upon ligand binding (e.g., Phe271, Phe329, Phe340, Arg319, Glu281). Altogether, the present study indicates that the molecular dynamic protocol is a consistent approach for managing LXRbeta-related induced fit process. This protocol could therefore be used for refining ligand docking solutions of a structure-based design strategy.
通过分子动力学研究了配体诱导契合现象在肝脏X受体β（LXRβ）的配体结合结构域的发生情况。从两个不同的LXRβ晶体复合物1PQ6B/GW和1PQ9B/T09测试了4纳秒轨迹的可靠性，这两个复合物分别以口袋的开放和关闭状态为特征。然后将交叉复合物1PQ6B/T09和1PQ9B/GW置于相同的分子动力学条件下，这些条件能够恢复与原始晶体学数据相似的LXRβ构象。对“开放到关闭”和“关闭到开放”构象转变的分析指出了配体结合口袋内衬关键残基在配体结合时参与局部重塑的动态作用（例如，苯丙氨酸271、苯丙氨酸329、苯丙氨酸340、精氨酸319、谷氨酸281）。总之，本研究表明分子动力学方案是处理LXRβ相关诱导契合过程的一种一致方法。因此，该方案可用于优化基于结构的设计策略的配体对接解决方案。
