Mutations adjacent to the end of transmembrane helices 6 and 7 independently affect drug efflux capacity of yeast ABC transporter Pdr5p.
Mutations adjacent to the end of transmembrane helices 6 and 7 independently affect drug efflux capacity of yeast ABC transporter Pdr5p.
复制标题
DOI：
10.1016/j.bbamem.2013.12.002
复制
发表时间：
2014-03
期刊：
影响因子：
--
通讯作者：
Zhigang Chen;Jingkai Li;Wei Wang;Xiaoxian Guo;Yongquan Li;X. Mao;Xinyu Chen;W. Guan
中科院分区：
文献类型：
--
作者：
Zhigang Chen;Jingkai Li;Wei Wang;Xiaoxian Guo;Yongquan Li;X. Mao;Xinyu Chen;W. Guan
作为哺乳动物p糖蛋白同源物，Pdr5p是酵母酵母细胞解毒的主要atp结合盒转运体。在这项研究中，两个新的功能丧失突变位于Pdr5p的预测跨膜螺旋的末端附近。C793F和S1230L突变显著削弱了Pdr5p的转运活性，但不影响ATPase活性和蛋白表达水平。结果表明，残基793的大小和残基1230的疏水性对Pdr5p的外排功能有重要影响。这表明位于跨膜螺旋末端的氨基酸残基在Pdr5p的药物外排中起重要作用。分子对接结果进一步表明，这两个单突变可能干扰了药物与Pdr5p之间的相互作用，阻止药物接近细胞内或细胞外的门静脉，从而阻止药物通过Pdr5p输出。
As a mammalian p-glycoprotein homolog, Pdr5p is a major ATP-binding cassette transporter for cellular detoxification in the yeastSaccharomyces cerevisiae. In this study, two novel loss-of-function mutations located adjacent to the ends of the predicted transmembrane helices of Pdr5p were identified. C793F and S1230L mutations considerably impaired the transport activity of Pdr5p without affecting the ATPase activity and the expression level of the protein. Our results demonstrate that the size of residue 793 and the hydrophobicity of residue 1230 are important for Pdr5p efflux function. It reveals that amino acid residues located near the end of transmembrane helix play an important role in drug efflux of Pdr5p. Molecular docking results further suggest that these two single mutations might have disturbed interactions between the drugs and Pdr5p, preventing the drugs from approaching the intracellular or extracellular portal and subsequently from being exported by Pdr5p.