Structure-function relationships of multidrug resistance P-glycoprotein.
The direct structure-function relationships of P-glycoprotein (P-gp) are presently unknown. In this paper two P-gp models are described: a homology model based on the Escherichia coli MsbA lipid transporter and a model based on the cross-linking results of Loo and Clarke. The pharmacophore pattern for the H-site (Hoechst 33342) is derived and binding sites on the transmembrane domains TM5 and TM11 are identified. Binding sites of rhodamines are also proposed on TM6 and TM12 in accordance with the published data. Location of the binding sites is opposite in both models, suggesting that TMs undergo rotation exposing the substrate bound from the membrane to the pore. It has been concluded that the models derived represent two different functional states of P-gp corresponding to nucleotide-free and nucleotide-bound P-gp. A qualitative correspondence to the P-gp crystallographic structure at 20 A resolution is found. A hypothesis is proposed about rearrangement of TMs upon state transition.
Pajeva
Ilza K
IK
Centre of Biomedical Engineering, Bulgarian Academy of Sciences, Academic George Bonchev Street Block 105, 1113 Sofia, Bulgaria.
Globisch
Christoph
C
Wiese
Michael
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry*; D000595:Amino Acid Sequence; D001562:Benzimidazoles / Q000737:chemistry; D018360:Crystallography, X-Ray; D018432:Drug Resistance, Multiple; D008958:Models, Molecular; D008969:Molecular Sequence Data
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001562:Benzimidazoles; C017807:bisbenzimide ethoxide trihydrochloride