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首页> 外文期刊>Biochimica et biophysica acta. Biomembranes >Multidrug ABC transporter Cdr1 of Candida albicans harbors specific and overlapping binding sites for human steroid hormones transport
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Multidrug ABC transporter Cdr1 of Candida albicans harbors specific and overlapping binding sites for human steroid hormones transport

机译：多rdrugABC Transporter CDR1的念珠菌蛋白质人类的母鸡特异性和重叠的人类类固醇激素运输的结合位点

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Abstract The present study examines the kinetics of steroids efflux mediated by the Candida drug resistance protein 1 (Cdr1p) and evaluates their interaction with the protein. We exploited our in-house mutant library for targeting the 252 residues forming the twelve transmembrane helices (TMHs) of Cdr1p. The screening revealed 65 and 58 residues critical for β-estradiol and corticosterone transport, respectively. Notably, up to 83% critical residues for corticosterone face the lipid interface compared to 54% for β-estradiol. Molecular docking identified a possible peripheral corticosterone-binding site made of 8/14 critical/non-critical residues between TMHs 3, 4 and 6. β-estradiol transport was severely hampered by alanine replacements of Cdr1p core residues involving TMHs 2, 5 and 8, in a binding site made of 10/14 critical residues mainly shared with rhodamine 6G with which it competes. By contrast, TMH11 was poorly impacted, although being part of the core domain. Finally, we observed the presence of several contiguous stretches of 3–5 critical residues in TMHs 2, 5 and 10 that points to a rotation motion of these helices during the substrate transport cycle. The selective structural arrangement of the steroid-binding pockets in the core region and at the lipid-TMD interface, which was never reported before, together with the possible rotation of some TMHs may be the structural basis of the drug-transport mechanism achieved by these type II ABC transporters. Graphical abstract Critical residues of Candida Cdr1p for β-estradiol (left) and corticosterone (right) transport highlight specific transport mechanisms. Display Omitted Highlights ? ABC transporter Cdr1p can transport human steroids, β-estradiol and corticosterone with high affinity ? The steroid interactive residues are scattered mostly at the periphery of TMHs 3, 4, 6, 9, 10, 12 ? pA, pC4 had good docking affinities and high number of critical residues for β-estradiol and corticosterone, respectively ? Many steroid interactive residues are vicinal, supporting the rotational movement of the helices during steroid transport ]]>
机译：摘要本研究检查了念珠菌耐药蛋白1（CDR1P）介导的类固醇流出的动力学，并评估它们与蛋白质的相互作用。我们利用我们的内部突变库，用于靶向形成CDR1P的12个跨膜螺旋（TMH）的252个残基。筛选揭示了β-雌二醇和皮质酮运输至关重要的65和58个残基。值得注意的是，高达83％的皮质酮临界残基面对脂质界面，而β-雌二醇的54％相比。分子对接鉴定出一种可能的外周皮质酮结合位点，由TMH 3,4和6.β-雌二醇转运之间的8/14临界/非关键残留物组成，含有CDR1P核酸残基的丙氨酸替代术后严重阻碍TMHS 2,5和8 ，在具有10/14关键残留物中的结合位点，主要与罗丹明6G分享，其中竞争。相比之下，TMH11受到影响不佳，尽管是核心领域的一部分。最后，我们观察到在基板传输循环期间指向这些螺旋的旋转运动的TMHS 2,5和10中的几种连续延伸的3-5个关键残留物的存在。在核心区域和脂质-TMD界面处的类固醇结合口袋的选择性结构布置在从未报道的脂质 - TMD界面以及某些TMH的可能旋转之上可以是由此实现的药物运输机制的结构基础II型ABC运输车。 β-雌二醇（左）和皮质酮（右）运输的图解摘要临界残留物突出特定运输机制。显示省略亮点？ ABC Transioner CDR1P可以用高亲和力运输人类类固醇，β-雌二醇和皮质酮？类固醇互动残留物主要散落在TMHS 3,4,6,9,10,12的周边？ PA，PC4分别对β-雌二醇和皮质酮的良好对接亲和力和大量关键残留物？许多类固醇交互式残留物都是邻近的，支持在类固醇运输过程中螺旋的旋转运动]]]>

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