Cargando…

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

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 o...

Descripción completa

Detalles Bibliográficos
Autores principales: Ravna, Aina W, Sylte, Ingebrigt, Sager, Georg
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747915/
https://www.ncbi.nlm.nih.gov/pubmed/19732422
http://dx.doi.org/10.1186/1742-4682-6-20
_version_ 1782172125562404864
author Ravna, Aina W
Sylte, Ingebrigt
Sager, Georg
author_facet Ravna, Aina W
Sylte, Ingebrigt
Sager, Georg
author_sort Ravna, Aina W
collection PubMed
description 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.
format Text
id pubmed-2747915
institution National Center for Biotechnology Information
language English
publishDate 2009
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-27479152009-09-22 Binding site of ABC transporter homology models confirmed by ABCB1 crystal structure Ravna, Aina W Sylte, Ingebrigt Sager, Georg Theor Biol Med Model Research 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. BioMed Central 2009-09-04 /pmc/articles/PMC2747915/ /pubmed/19732422 http://dx.doi.org/10.1186/1742-4682-6-20 Text en Copyright © 2009 Ravna et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 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.
spellingShingle Research
Ravna, Aina W
Sylte, Ingebrigt
Sager, Georg
Binding site of ABC transporter homology models confirmed by ABCB1 crystal structure
title Binding site of ABC transporter homology models confirmed by ABCB1 crystal structure
title_full Binding site of ABC transporter homology models confirmed by ABCB1 crystal structure
title_fullStr Binding site of ABC transporter homology models confirmed by ABCB1 crystal structure
title_full_unstemmed Binding site of ABC transporter homology models confirmed by ABCB1 crystal structure
title_short Binding site of ABC transporter homology models confirmed by ABCB1 crystal structure
title_sort binding site of abc transporter homology models confirmed by abcb1 crystal structure
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747915/
https://www.ncbi.nlm.nih.gov/pubmed/19732422
http://dx.doi.org/10.1186/1742-4682-6-20
work_keys_str_mv AT ravnaainaw bindingsiteofabctransporterhomologymodelsconfirmedbyabcb1crystalstructure
AT sylteingebrigt bindingsiteofabctransporterhomologymodelsconfirmedbyabcb1crystalstructure
AT sagergeorg bindingsiteofabctransporterhomologymodelsconfirmedbyabcb1crystalstructure