Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California, USA.
Nat Chem Biol. 2012 Feb 19;8(4):342-9. doi: 10.1038/nchembio.796.
Human cholesteryl ester transfer protein (CETP) mediates the net transfer of cholesteryl ester mass from atheroprotective high-density lipoproteins to atherogenic low-density lipoproteins by an unknown mechanism. Delineating this mechanism would be an important step toward the rational design of new CETP inhibitors for treating cardiovascular diseases. Using EM, single-particle image processing and molecular dynamics simulation, we discovered that CETP bridges a ternary complex with its N-terminal β-barrel domain penetrating into high-density lipoproteins and its C-terminal domain interacting with low-density lipoprotein or very-low-density lipoprotein. In our mechanistic model, the CETP lipoprotein-interacting regions, which are highly mobile, form pores that connect to a hydrophobic central cavity, thereby forming a tunnel for transfer of neutral lipids from donor to acceptor lipoproteins. These new insights into CETP transfer provide a molecular basis for analyzing mechanisms for CETP inhibition.
人载脂蛋白酯酶转移蛋白（CETP）通过未知机制介导胆固醇酯质量从保护性高密度脂蛋白向致动脉粥样硬化性低密度脂蛋白的净转移。阐明这一机制将是合理设计用于治疗心血管疾病的新型 CETP 抑制剂的重要步骤。通过 EM、单颗粒图像处理和分子动力学模拟，我们发现 CETP 与三元复合物桥接，其 N 端β-桶结构域穿透进入高密度脂蛋白，其 C 端结构域与低密度脂蛋白或极低密度脂蛋白相互作用。在我们的机制模型中，CETP 脂蛋白相互作用区域高度移动，形成连接到疏水性中心腔的孔，从而形成从供体脂蛋白到受体脂蛋白转移中性脂质的隧道。这些对 CETP 转移的新见解为分析 CETP 抑制机制提供了分子基础。
