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ATP结合盒(ABC)转运蛋白中的多药耐药相关蛋白MRP4与多药耐药性的产生有关。多药耐药性的产生对于抗肿瘤和抗感染的治疗是一个很大的挑战。在一些MRP4高表达的肿瘤中,抑制MRP4的作用对影响肿瘤的进程和药物的耐药性都有显著效果。由于MRP4的结构信息非常有限,缺少X-射线晶体结构,同源模建是获得MRP4三维结构的一种有效的方法。我们主要基于秀丽隐杆线虫(Caenorhabditis elegans)的P-gp,海栖热胞菌(Thermotoga maritima)的ABC转运蛋白TM287/288及金黄色葡萄球菌(Staphylococcus aureus)的ABC转运蛋白Sav1866的结构分别建立了人MRP4的底物摄取态、底物转运态和底物释放态模型。模建的结构进一步进行能量最小化和分子动力学模拟优化,经过多种工具和服务器的验证证明了模建结构的合理性和可靠性。这些MRP4的结构可以用来研究MRP4结构和功能的关系,以及设计特定的膜转运蛋白调节剂(MTMA)。
Multidrug resistance-associated protein MRP4 in the ATP-binding cassette (ABC) transporter is involved in multidrug resistance. Multidrug resistance is a great challenge for the treatment of anti-tumor and anti-infection. In some MRP4 overexpressing tumors, the inhibition of MRP4 has a significant effect on tumor progression and drug resistance. Due to the very limited structure information of MRP4 and the lack of X-ray crystal structure, homology modeling is an effective method to obtain MRP4 three-dimensional structure. We constructed, respectively, based primarily on the structures of P-gp of Caenorhabditis elegans, ABC transporter TM287 / 288 of Thermotoga maritima and ABC transporter Sav1866 of Staphylococcus aureus The substrate uptake status, substrate transport status, and substrate release status of human MRP4 were modeled. The modeled structure is further optimized for energy minimization and molecular dynamics simulation. The validation of a variety of tools and servers proves the rationality and reliability of the modeled structure. The structure of these MRP4s can be used to study the relationship between MRP4 structure and function, as well as the design of specific membrane transporter modulators (MTMAs).