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Binding site of ABC transporter homology models confirmed by ABCB1 crystal structure.

Ravna AW, Sylte I, Sager G - Theor Biol Med Model (2009)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Pharmacology and Toxicology, Institute of Medical Biology, Faculty of Health Sciences, University of Tromsø, N-9037 Tromsø, Norway. Aina.W.Ravna@uit.no

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.

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Overall domain topology of ABCB1, ABCC4 and ABCC5.
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Figure 1: Overall domain topology of ABCB1, ABCC4 and ABCC5.

Mentions: 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 substrates out of the cell.


Binding site of ABC transporter homology models confirmed by ABCB1 crystal structure.

Ravna AW, Sylte I, Sager G - Theor Biol Med Model (2009)

Overall domain topology of ABCB1, ABCC4 and ABCC5.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2747915&req=5

Figure 1: Overall domain topology of ABCB1, ABCC4 and ABCC5.
Mentions: 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 substrates out of the cell.

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Pharmacology and Toxicology, Institute of Medical Biology, Faculty of Health Sciences, University of Tromsø, N-9037 Tromsø, Norway. Aina.W.Ravna@uit.no

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.

Show MeSH
Related in: MedlinePlus