Molecular basis of the polyspecificity of P-glycoprotein (ABCB1): recent biochemical and structural studies.
Molecular basis of the polyspecificity of P-glycoprotein (ABCB1): recent biochemical and structural studies.
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P-糖蛋白多蛋白多蛋白多蛋白的分子基础（ABCB1）：最近的生化和结构研究。
DOI：
10.1016/bs.acr.2014.10.003
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发表时间：
2015
影响因子：
--
通讯作者：
Ambudkar SV
中科院分区：
文献类型：
--
作者：
Chufan EE;Sim HM;Ambudkar SV
ABCB1 （p -糖蛋白/P-gp）是一种atp结合盒转运蛋白，因其与癌细胞的多药耐药有关而闻名。由ATP的水解提供动力，它流出结构多样的化合物。在本章中，我们讨论了目前对P-gp底物多特异性的分子基础的看法。解释这种性质的特征之一是在P-gp中观察到的结构柔韧性。最近发表了几种小鼠P-gp的x射线晶体结构，在缺乏核苷酸的情况下，有或没有结合抑制剂。所有的结构都是一个内向的构象，表现出不同程度的结构域分离，从而揭示了一个高度灵活的蛋白质。生物化学和生物物理研究也证明了小鼠和人类P-gp的这种灵活性。定点诱变揭示了P-gp中存在针对单一底物的多个转运活性结合位点。因此，药物可以在一级或二级位点结合。生化、分子模型和结构-活性关系研究表明，一个大的、常见的药物结合袋具有不同底物的重叠位点。我们认为，除了结构的灵活性，分子或化学的灵活性也有助于底物与多个位点的结合，形成多特异性的基础。
ABCB1 (P-glycoprotein/P-gp) is an ATP-binding cassette transporter well known for its association with multidrug resistance in cancer cells. Powered by the hydrolysis of ATP, it effluxes structurally diverse compounds. In this chapter, we discuss current views on the molecular basis of the substrate polyspecificity of P-gp. One of the features that accounts for this property is the structural flexibility observed in P-gp. Several X-ray crystal structures of mouse P-gp have been published recently in the absence of nucleotide, with and without bound inhibitors. All the structures are in an inward-facing conformation exhibiting different degrees of domain separation, thus revealing a highly flexible protein. Biochemical and biophysical studies also demonstrate this flexibility in mouse as well as human P-gp. Site-directed mutagenesis has revealed the existence of multiple transport-active binding sites in P-gp for a single substrate. Thus, drugs can bind at either primary or secondary sites. Biochemical, molecular modeling, and structure-activity relationship studies suggest a large, common drug-binding pocket with overlapping sites for different substrates. We propose that in addition to the structural flexibility, the molecular or chemical flexibility also contributes to the binding of substrates to multiple sites forming the basis of polyspecificity.
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影响因子：
4.3
作者：
Dolghih E;Bryant C;Renslo AR;Jacobson MP
通讯作者：
Jacobson MP
影响因子：
8
作者：
Li, Jingzhi;Jaimes, Kimberly F.;Aller, Stephen G.
通讯作者：
Aller, Stephen G.
DOI：
10.1126/science.1246489
发表时间：
2014-03-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Lee JY;Yang JG;Zhitnitsky D;Lewinson O;Rees DC
通讯作者：
Rees DC
DOI：
10.1126/science.1168750
发表时间：
2009-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Aller SG;Yu J;Ward A;Weng Y;Chittaboina S;Zhuo R;Harrell PM;Trinh YT;Zhang Q;Urbatsch IL;Chang G
通讯作者：
Chang G
影响因子：
64.8
作者：
Dawson, Roger J. P.;Locher, Kaspar P.
通讯作者：
Locher, Kaspar P.