Molecular model of the outward facing state of the human multidrug resistance protein 4 (MRP4/ABCC4)

doi:10.1016/j.bmcl.2008.05.047

Bioorganic & Medicinal Chemistry Letters

Volume 18, Issue 12, 15 June 2008, Pages 3481-3483

https://doi.org/10.1016/j.bmcl.2008.05.047 Get rights and content

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 cancer and infections. We have constructed a molecular model of ABCC4 based on the outward facing Sav1866 crystal structure using molecular modeling techniques. Amino acids reported by ICMPocketFinder to take part in substrate translocation were among others Glu103 (TMH1), Ser328 (TMH5), Gly359 (TMH6), Arg362 (TMH6), Val726 (TMH7), and Leu987 (TMH12), and their corresponding amino acids in ABCB1 (P-glycoprotein) have been reported to be involved in drug binding according to site-directed mutagenesis studies. The ABCC4 model may be used as a working tool for experimental studies on ABCC4 and design of more specific membrane transport modulating agents (MTMA).

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Acknowledgment

This study was supported with Grants from the Norwegian Cancer Society.

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Citation Excerpt :
ECLs and ICLs are the extra- and intra-cytoplasmic loops connecting the TMHs with each other, and ICD 1 and 2 are two intra-cytoplasmic domains (covalently) connecting TMDs and NBDs. Although pure homology molecular models can document on the different domains [8–13], they do not include the surrounding lipid bilayer and a sufficient (dynamic) conformational sampling. In the current study, we used homology modeling to construct the human wild-type (WT) MRP4 protein in its inward-facing (IF) conformer (i.e., drug chamber open towards inner compartment) and in its ligand-free (apo) state.
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Molecular model of the outward facing state of the human multidrug resistance protein 4 (MRP4/ABCC4)

Abstract

Graphical abstract

Section snippets

Acknowledgment

Adv. Drug. Deliv. Rev.

J. Urol.

Neuroscience

Hepatology

Blood

Meth. Enzymol.

J. Mol. Biol.

J. Biol. Chem.