Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding.
P-glycoprotein (P-gp) detoxifies cells by exporting hundreds of chemically unrelated toxins but has been implicated in multidrug resistance (MDR) in the treatment of cancers. Substrate promiscuity is a hallmark of P-gp activity, thus a structural description of poly-specific drug-binding is important for the rational design of anticancer drugs and MDR inhibitors. The x-ray structure of apo P-gp at 3.8 angstroms reveals an internal cavity of approximately 6000 angstroms cubed with a 30 angstrom separation of the two nucleotide-binding domains. Two additional P-gp structures with cyclic peptide inhibitors demonstrate distinct drug-binding sites in the internal cavity capable of stereoselectivity that is based on hydrophobic and aromatic interactions. Apo and drug-bound P-gp structures have portals open to the cytoplasm and the inner leaflet of the lipid bilayer for drug entry. The inward-facing conformation represents an initial stage of the transport cycle that is competent for drug binding.
Aller
Stephen G
SG
Department of Molecular Biology, Scripps Research Institute, 10550 North Torrey Pines Road, CB105, La Jolla, CA 92037, USA.
Yu
Jodie
J
Ward
Andrew
A
Weng
Yue
Y
Chittaboina
Srinivas
S
Zhuo
Rupeng
R
Harrell
Patina M
PM
Trinh
Yenphuong T
YT
Zhang
Qinghai
Q
Urbatsch
Ina L
IL
Chang
Geoffrey
G