Binding site of ABC transporter homology models confirmed by ABCB1 crystal structure
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Binding site of ABC transporter homology models confirmed by ABCB1 crystal structure Aina W Ravna*, Ingebrigt Sylte and Georg Sager Address: Department of Medical Pharmacology and Toxicology, Institute of Medical Biology, Faculty of Health Sciences, University of Tromsø, N-9037 Tromsø, Norway Email: Aina W Ravna* - [email protected]; Ingebrigt Sylte - [email protected]; Georg Sager - [email protected] * Corresponding author
Published: 4 September 2009 Theoretical Biology and Medical Modelling 2009, 6:20
doi:10.1186/1742-4682-6-20
Received: 4 June 2009 Accepted: 4 September 2009
This article is available from: http://www.tbiomed.com/content/6/1/20 © 2009 Ravna et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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 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.
Introduction 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 [1-3]. Since ABC genes are highly conserved between species, it is likely that most of these genes have been present since the beginning of eukaryotic evolution [4]. The overall topology of ABCB1, ABCC4 and ABCC5 is divided into transmembrane domain 1 (TMD1) - nucleotide-binding domain 1 (NBD1) - TMD2 - NBD2 (Figure
1). 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 subs
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