title: Structural and dynamic perspectives on the promiscuous transport activity of P-glycoprotein.
abstract: The multidrug transporter P-glycoprotein (P-gp) is expressed in the blood-brain barrier endothelium where it effluxes a range of drug substrates, preventing their accumulation within the brain. P-gp has been studied extensively for 40 years because of its crucial role in the absorption, distribution, metabolism and elimination of a range of pharmaceutical compounds. Despite this, many aspects of the structure-function mechanism of P-gp are unresolved. Here we review the emerging role of molecular dynamics simulation techniques in our understanding of the membrane-embedded conformation of P-gp. We discuss its conformational plasticity in the presence and absence of ATP, and recent efforts to characterize the drug binding sites and uptake pathways.
authors.affiliation: Research School of Chemistry (RSC), The Australian National University, Canberra, ACT, 2601, Australia.
authors.forename: Nandhitha
authors.initials: N
authors.lastname: Subramanian
authors.affiliation: School of Chemistry and Molecular Biosciences (SCMB), University of Queensland, Brisbane, QLD, 4072, Australia.
authors.forename: Karmen
authors.initials: K
authors.lastname: Condic-Jurkic
authors.affiliation: Research School of Chemistry (RSC), The Australian National University, Canberra, ACT, 2601, Australia. Electronic address: megan.o'mara@anu.edu.au.
authors.forename: Megan L
authors.initials: ML
authors.lastname: O'Mara
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D001693:Biological Transport, Active; D006801:Humans; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000255:Adenosine Triphosphate
keywords: ABC (ATP-binding cassette) transporter; Molecular dynamics simulation; Multidrug transporter; P-glycoprotein; Substrate transport