Molecular models of different states of the human multidrug resistance protein 4(MRP4/ABCC4)

人多药耐药相关蛋白MRP4不同状态的分子模型（英文）

ATP-binding cassette（ABC） transporter multidrug resistance protein 4（MRP4, ABCC4） is involved in multidrug resistance（MDR）, which is an increasing challenge to the treatment of cancers and infections. MRP4 is overexpressed in several types of cancers, and MRP4 inhibition shows striking effects against cancer progression and drug resistance. However, the structural knowledge of this protein remains unclear due to lack of an MRP4 X-ray structure, and homology modeling approach is an effective way to obtain three-dimensional structure of MRP4. We constructed three molecular models of human MRP4 mainly based on the inward facing Caenorhabditis elegans P-glycoprotein（P-gp）, the Thermotoga maritima heterodimeric ABC transporter TM287-TM288（TM287/288） and the outward facing Staphylococcus aureus Sav1866 crystal structures, which represented substrate uptake, transport and release state, respectively. The structures were further energy minimized and optimized by molecular dynamic simulations（MDS）. All the models were validated by various tools and servers, and the results showed that the quality of the models was reasonable and acceptable. These MRP4 models could be used as working tools for experimental studies on the structure and functions of MRP4 and designing more specific membrane transport modulating agents（MTMA）.

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)。