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Structure-function analysis of multidrug transporters in Lactococcus lactis
H W van Veen1, M Putman, A Margolles
1Department of Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Kerklaan 30, NL-9751 NN, Haren, The Netherlands. h.w.van.veen@biol.rug.nl
Abstract:
The active extrusion of cytotoxic compounds from the cell by multidrug transporters is one of the major causes of failure of chemotherapeutic treatment of tumor cells and of infections by pathogenic microorganisms. A multidrug transporter in Lactococcus lactis, LmrA, is a member of the ATP-binding cassette (ABC) superfamily and a bacterial homolog of the human multidrug resistance P-glycoprotein. Another multidrug transporter in L. lactis, LmrP, belongs to the major facilitator superfamily, and is one example of a rapidly expanding group of secondary multidrug transporters in microorganisms. Thus, LmrA and LmrP are transport proteins with very different protein structures, which use different mechanisms of energy coupling to transport drugs out of the cell. Surprisingly, both proteins have overlapping specificities for drugs, are inhibited by the same set of modulators, and transport drugs via a similar transport mechanism. The structure-function relationships that dictate drug recognition and transport by LmrP and LmrA represent an intriguing area of research.
Insights
Multidrug transporters like LmrA and LmrP in Lactococcus lactis, despite structural differences, share drug specificities and transport mechanisms. Understanding these bacterial multidrug transporters is key to overcoming treatment failures.
Area of Science:
- Microbiology
- Molecular Biology
- Biochemistry
Background:
- Multidrug transporters actively expel cytotoxic compounds, contributing to chemotherapy failure and antimicrobial resistance.
- Lactococcus lactis possesses two key multidrug transporters: LmrA (ABC superfamily) and LmrP (major facilitator superfamily).
- These transporters, LmrA and LmrP, exhibit distinct structures and energy coupling mechanisms.
Purpose of the Study:
- To investigate the surprising similarities in drug specificity and transport mechanisms between LmrA and LmrP.
- To explore the structure-function relationships governing drug recognition and transport by these bacterial multidrug transporters.
Main Methods:
- Comparative analysis of LmrA and LmrP structures and functions.
- Studies on drug specificities and modulator inhibition profiles.
- Investigation of transport mechanisms employed by both proteins.
Main Results:
- LmrA and LmrP, despite differing in protein structure and energy coupling, exhibit overlapping drug specificities.
- Both transporters are inhibited by the same set of modulators.
- Surprisingly, LmrA and LmrP utilize similar drug transport mechanisms.
Conclusions:
- Bacterial multidrug transporters LmrA and LmrP display convergent functional properties despite divergent evolutionary origins and structural architectures.
- The shared drug recognition and transport mechanisms highlight potential common principles in multidrug extrusion across different transporter families.
- Further research into these structure-function relationships is crucial for understanding and potentially overcoming multidrug resistance.