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Structure-function relationships of multidrug resistance P-glycoprotein
Ilza K Pajeva1, Christoph Globisch, Michael Wiese
1Centre of Biomedical Engineering, Bulgarian Academy of Sciences, Academic George Bonchev Street Block 105, 1113 Sofia, Bulgaria.
Journal of Medicinal Chemistry
|April 30, 2004
Summary
Two P-glycoprotein (P-gp) models reveal distinct functional states, suggesting transmembrane domain rearrangement upon nucleotide binding. This advances understanding of P-gp structure-function relationships.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Pharmacology
Background:
- Direct structure-function relationships of P-glycoprotein (P-gp) remain elusive.
- P-gp is a crucial transporter involved in drug efflux and multidrug resistance.
Purpose of the Study:
- To develop and analyze two distinct models of P-gp.
- To elucidate the binding sites and functional states of P-gp.
Main Methods:
- Homology modeling based on Escherichia coli MsbA.
- Modeling derived from cross-linking data (Loo and Clarke).
- Pharmacophore pattern derivation for H-site (Hoechst 33342) and rhodamine binding site identification.
Main Results:
- Identified potential binding sites on transmembrane domains (TMs) TM5, TM11, TM6, and TM12 for substrates like Hoechst 33342 and rhodamines.
- Proposed that TMs undergo rotation, exposing bound substrates from the membrane to the pore.
- Models suggest distinct functional states: nucleotide-free and nucleotide-bound P-gp.
Conclusions:
- The derived models represent different functional states of P-gp.
- A hypothesis on transmembrane domain rearrangement during state transitions is proposed.
- Qualitative agreement with low-resolution P-gp crystallographic structure observed.