dc.description.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 <i>Escherichia coli</i> 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 crosslinking
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 sitedirected
mutagenesis studies. The ABCB1, ABCC4 and ABCC5 models display distinct differences
in the electrostatic properties of their drug recognition sites. | en |