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On the mechanism of promiscuous ligand-binding by multidrug resistance regulator LmrR and structural investigations of lytic transglycosylase MltF

25 May 2012

PhD ceremony: Mr. P.K. Madoori, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: On the mechanism of promiscuous ligand-binding by multidrug resistance regulator LmrR and structural investigations of lytic transglycosylase MltF

Promotor(s): prof. B.W. Dijkstra

Faculty: Mathematics and Natural Scienes

LmrR (Lactococcal multidrug resistance Regulator) is a protein required by Lactococcus lactis to survive in the presence of toxic compounds. In response to chemically diverse compounds like ethidium and daunomycin, LmrR enhances the production of the major multidrug transporter LmrCD, which excretes the toxic compounds, thus preventing them to reach their cellular targets.

Crystal structures of LmrR in a drug-free state and with several bound drugs, as presented in this thesis, reveal the key structural determinants of its multidrug specificity. The LmrR structure contains a typical β-winged helix-turn-helix domain with an additional C-terminal helix involved in dimerization. Its dimeric organization is highly unusual with a hydrophobic pore at the dimer centre harbouring the multidrug-binding site. Planar lipophilic drugs bind in a similar manner with their aromatic rings sandwiched in between the indole groups of two dimer-related tryptophan residues. The use of a single site for binding different ligands, instead of a large binding site with partially overlapping subsites, and the dominating role of the dyad-related tryptophan residues in drug recognition and binding, distinguish LmrR from other well-characterized multidrug related transcriptional regulators.

Last modified:13 March 2020 01.00 a.m.
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