Abstract
The human ATP-binding cassette (ABC) transporters ABCB1, ABCC4 and ABCC5 are involved in resistance to chemotherapeutic agents. Here we present molecular models of ABCB1, ABCC4 and ABCC5 by homology based on a wide open inward-facing conformation of Escherichia coli MsbA, which were constructed in order to elucidate differences in the electrostatic and molecular features of their drug recognition conformations. As a quality assurance of the methodology, the ABCB1 model was compared to an ABCB1 X-ray crystal structure, and with published cross-linking and site directed mutagenesis data of ABCB1. Amino acids Ile306 (TMH5), Ile340 (TMH6), Phe343 (TMH6), Phe728 (TMH7), and Val982 (TMH12), form a putative substrate recognition site in the ABCB1 model, which is confirmed by both the ABCB1 X-ray crystal structure and the site-directed mutagenesis studies. The ABCB1, ABCC4 and ABCC5 models display distinct differences in the electrostatic properties of their drug recognition sites.
Highlights
The human ATP-binding cassette (ABC) transporters ABCB1, ABCC4 and ABCC5 belong to the ABC superfamily, a subgroup of Primary active transporters [1]
The overall topology of ABCB1, ABCC4 and ABCC5 is divided into transmembrane domain 1 (TMD1) - nucleotide-binding domain 1 (NBD1) - TMD2 - NBD2
We present molecular models of ABCB1, ABCC4 and ABCC5 based on a wide open inward-facing conformation of Escherichia coli MsbA [19]
Summary
The human ATP-binding cassette (ABC) transporters ABCB1, ABCC4 and ABCC5 belong to the ABC superfamily, a subgroup of Primary active transporters [1]. The transporters in the ABC superfamily are structurally related membrane proteins that have a common intracellular motif that exhibits ATPase activity. This motif cleaves ATP's terminal phosphate to energize the transport of molecules from regions of low concentration to regions of high concentration [1,2,3]. The Walker A, or phosphate binding loop (P-loop), and Walker B motifs, are localized in the NBDs, while the TMDs contribute to the substrate translocation events (recognition, translocation and release). ABCB1, ABCC4 and ABCC5 are exporters, pumping substrates out of the cell
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
