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

• Main Authors: Sager Georg, Sylte Ingebrigt, Ravna Aina W
• Format: Article
• Language: English
• Published: BMC 2009-09-01
• Series: Theoretical Biology and Medical Modelling
• Online Access: http://www.tbiomed.com/content/6/1/20

<p>Abstract</p> <p>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 <it>Escherichia coli </it>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.</p>