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Structure of the ligand-blocked periplasmic entrance of the bacterial multidrug efflux protein TolC.

Abstract：

:The trimeric TolC protein of Escherichia coli comprises an outer membrane beta-barrel and a contiguous alpha-helical barrel projecting across the periplasm. This provides a single 140 A long pore for multidrug efflux and protein export. We have previously reported that trivalent cations such as hexammine cobalt can severely inhibit the conductivity of the TolC pore reconstituted in planar lipid bilayers. Here, isothermal calorimetry shows that Co(NH(3))(6)(3+) binds to TolC with an affinity of 20 nM. The crystal structure of the TolC-Co(NH(3))(6)(3+) complex was determined to 2.75 A resolution, and showed no significant difference in the protein when compared with unliganded TolC. An electron density difference map revealed that a single ligand molecule binds at the centre of the periplasmic entrance, the sole constriction of TolC. The octahedral symmetry of the ligand and the three-fold rotational symmetry of the TolC entrance determine a binding site in which the ligand forms hydrogen bonds with the Asp(374) residue of each monomer. When Asp(374) was substituted by alanine, high affinity ligand binding was abolished and inhibition of TolC pore conductivity in lipid bilayers was alleviated. Comparable effects followed independent substitution of the neighbouring Asp(371), indicating that this aspartate ring also contributes to the high affinity ligand binding site. As the electronegative entrance is widely conserved in the TolC family, it may be a useful target for the development of inhibitors against multidrug resistant pathogenic bacteria.

journal_name

J Mol Biol

journal_title

Journal of molecular biology

authors

Higgins MK,Eswaran J,Edwards P,Schertler GF,Hughes C,Koronakis V

doi

10.1016/j.jmb.2004.07.088

keywords:

subject

Has Abstract

pub_date

2004-09-17 00:00:00

pages

697-702

issue

3

eissn

0022-2836

issn

1089-8638

pii

S0022-2836(04)00928-3

journal_volume

342

pub_type

杂志文章

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