Molecular models of different states of the human multidrug resistance protein 4(MRP4/ABCC4)
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-glyeoprotein(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).
MRP4 Homology modeling Molecular dynamic simulations
Ya Chen Hongwei Jin Liangren Zhang Zhenming Liu
State Key Laboratory of Natural and Biomimetic Drugs.School of Pharmaceutical Sciences,Peking University Health Science Center,Beijing 100191,China
国内会议
大连
英文
577-586
2016-09-24（万方平台首次上网日期，不代表论文的发表时间）