TY - JOUR
T1 - Structural and dynamic perspectives on the promiscuous transport activity of P-glycoprotein
AU - Subramanian, Nandhitha
AU - Condic-Jurkic, Karmen
AU - O'Mara, Megan L.
N1 - Publisher Copyright:
© 2016 Elsevier Ltd
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
KW - ABC (ATP-binding cassette) transporter
KW - Molecular dynamics simulation
KW - Multidrug transporter
KW - P-glycoprotein
KW - Substrate transport
UR - http://www.scopus.com/inward/record.url?scp=84969974206&partnerID=8YFLogxK
U2 - 10.1016/j.neuint.2016.05.005
DO - 10.1016/j.neuint.2016.05.005
M3 - Review article
SN - 0197-0186
VL - 98
SP - 146
EP - 152
JO - Neurochemistry International
JF - Neurochemistry International
ER -