1. New light on multidrug binding by an ATP-binding-cassette transporter
- Author
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Saroj Velamakanni, Hendrik W. van Veen, Henrietta Venter, Barbara Woebking, Akanksha Bapna, Richard A. Shilling, and Sanjay Shahi
- Subjects
Models, Molecular ,Molecular Sequence Data ,Antineoplastic Agents ,ATP-binding cassette transporter ,Biology ,Toxicology ,Protein structure ,Animals ,Humans ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Amino Acid Sequence ,Homology modeling ,Peptide sequence ,ATP-binding domain of ABC transporters ,Pharmacology ,Genetics ,chemistry.chemical_classification ,Binding Sites ,Biological Transport ,Transporter ,Drug Resistance, Multiple ,Protein Structure, Tertiary ,Amino acid ,Multiple drug resistance ,Biochemistry ,chemistry ,Drug Resistance, Neoplasm ,Mutation ,ATP-Binding Cassette Transporters - Abstract
ATP-binding-cassette (ABC) multidrug transporters confer multidrug resistance to pathogenic microorganisms and human tumour cells by mediating the extrusion of structurally unrelated chemotherapeutic drugs from the cell. The molecular basis by which ABC multidrug transporters bind and transport drugs is far from clear. Genetic analyses during the past 14 years reveal that the replacement of many individual amino acids in mammalian multidrug resistance P-glycoproteins can affect cellular resistance to drugs, but these studies have failed to identify specific regions in the primary amino acid sequence that are part of a defined drug-binding pocket. The recent publication of an X-ray crystallographic structure of the bacterial P-glycoprotein homologue MsbA and an MsbA-based homology model of human P-glycoprotein creates an opportunity to compare the original mutagenesis data with the three-dimensional structures of transporters. Our comparisons reveal that mutations that alter specificity are present in three-dimensional 'hotspot' regions in the membrane domains of P-glycoprotein.
- Published
- 2006