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

doi:10.5246/jcps.2016.06.048

Journal of Chinese Pharmaceutical Sciences ›› 2016, Vol. 25 ›› Issue (6): 428-437.DOI: 10.5246/jcps.2016.06.048

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

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

Received:2016-04-15 Revised:2016-04-30 Online:2016-06-29 Published:2016-05-13
Contact: Tel. +86-010-82802567, +86-010-82805514, E-mail: liangren@bjmu.edu.cn, zmliu@bjmu.edu.cn
Supported by:
National High Technology Research and Development Program 863 (Grant No. 2012AA020308), National Natural Science Foundation of China (Grant No. 21272017).

Abstract

Abstract:

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 structuralknowledge of this protein remains unclear due to lack of an MRP4 X-ray structure, and homology modeling approach is an effectiveway 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).

Key words: MRP4, Homology modeling, Molecular dynamic simulations

CLC Number:

R916

Supporting:

Ya Chen, Hongwei Jin, Liangren Zhang, Zhenming Liu. Molecular models of different states of the human multidrug resistance protein 4 (MRP4/ABCC4)[J]. Journal of Chinese Pharmaceutical Sciences, 2016, 25(6): 428-437.

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

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