胆固醇酯转移蛋白在胆固醇酯转移中的结构与功能  

Structure and Function of Cholesteryl Ester Transfer Protein in Transferring Cholesteryl Ester

作　　者：雷东升[1,2] 童慧敏 张磊 张星[1,2] 张胜利[1] 任罡 

机构地区：[1]西安交通大学理学院应用物理系,西安710049 [2]The Molecular Foundry,Lawrence Berkeley National Laboratory

出　　处：《化学进展》2014年第5期879-888,共10页Progress in Chemistry

基　　金：美国能源部基础科学基金资助项目(DE-AC02-05CH11231);美国国立卫生研究院(NIH)基金资助项目(NHLBI 1R01HL115153);中国国家自然科学基金项目(No.11074196;11374237)资助~~

摘　　要：人体胆固醇酯转移蛋白(CETP)会造成胆固醇酯从高密度脂蛋白(HDL)向低密度脂蛋白(LDL)或极低密度脂蛋白(VLDL)的转移,从而增加人体患心血管疾病的危险性。了解CETP在胆固醇酯转移过程中的作用和机理,是研发新的CETP抑制剂药物以预防和治疗心血管疾病的重要基础和关键步骤。本文综述了CETP结构与功能领域研究的最新进展,详细介绍了CETP与各类脂蛋白绑定结构的高分辨透射电子显微镜研究;并结合对CETP晶体结构的分析,以及生理溶液中CETP结构与动态特征、CETP与脂滴间相互作用的分子动力学模拟研究结果,阐述并讨论了CETP脂转移机理的"通道"模型;最后对尚待解决的关键问题与未来的研究方向进行了展望,以期促进CETP功能机理的研究和抑制药物的研制。Cardiovascular diseases（ CVDs） are the leading cause of death worldwide. Human cholesteryl esters（ CEs） are naturally transferred from atheroprotective high-density lipoproteins（ HDLs） to atherogenic lowdensity lipoproteins（ LDLs） and very low-density lipoproteins（ VLDLs） by cholesteryl ester transfer protein（ CETP）,resulting in a higher probability of CVDs. Finding out the mechanism of CETP in CE transport is an important basis for designing new CETP inhibitors for treating CVDs. This review is focused on the recent studies of CETP structure and interactions w ith lipoproteins. Transmission electron microscopy（ TEM） studies show ed that CETP not only can bind to HDL,LDL and VLDL into binary complexes,respectively,but also connects HDL and LDL or VLDL into a ternary complex via penetrating into the HDL core w ith its N-terminal domain and the LDL or VLDL surface w ith its C-terminal domain. Molecular dynamics simulations suggested that the penetrated distal ends are highly flexible under physiological conditions and w hen CETP contacts lipid droplets. This flexibility allow s for large-scale conformational changes,and can even open pores in the distalends. These pores and the original hydrophobic cavities w ithin the CETP crystal structure are generally stable in physiological solution,and can even connect together into a continuous tunnel for CE transfer. Based on above results,scientists introduced and discussed the ＂tunnel＂model for CETP-mediated lipid transfer in detail,and further suggested new interfaces of CETP for being targeted by a new generation CETP inhibitors to treat CVDs.

关 键 词：胆固醇酯 胆固醇酯转移蛋白 脂蛋白 透射电子显微镜 分子动力学模拟 结构柔性 通道模型 

分 类 号：Q51[生物学—生物化学] Q591.5