Toward Understanding the Outer Membrane Uptake of Small Molecules by Pseudomonas aeruginosa

被引:47
作者
Eren, Elif [1 ]
Parkin, Jamie [2 ]
Adelanwa, Ayodele [1 ]
Cheneke, Belete [3 ]
Movileanu, Liviu [3 ]
Khalid, Syma [2 ]
van den Berg, Bert [1 ]
机构
[1] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA
[2] Univ Southampton, Sch Chem, Syst & Synthet Biol Modelling Grp, Southampton SO17 1BJ, Hants, England
[3] Syracuse Univ, Dept Phys, Syracuse, NY 13244 USA
基金
英国工程与自然科学研究理事会; 美国国家科学基金会; 美国国家卫生研究院;
关键词
GRAM-NEGATIVE BACTERIA; AUTOMATED DOCKING; EFFLUX PUMPS; ACINETOBACTER-BAUMANNII; MULTIDRUG-RESISTANCE; DYNAMICS SIMULATIONS; CRYSTAL-STRUCTURES; ESCHERICHIA-COLI; FORCE-FIELD; CHANNEL;
D O I
10.1074/jbc.M113.463570
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Because small molecules enter Gram-negative bacteria via outer membrane (OM) channels, understanding OM transport is essential for the rational design of improved and new antibiotics. In the human pathogen Pseudomonas aeruginosa, most small molecules are taken up by outer membrane carboxylate channel (Occ) proteins, which can be divided into two distinct subfamilies, OccD and OccK. Here we characterize substrate transport mediated by Occ proteins belonging to both subfamilies. Based on the determination of the OccK2-glucuronate co-crystal structure, we identify the channel residues that are essential for substrate transport. We further show that the pore regions of the channels are rigid in the OccK subfamily and highly dynamic in the OccD subfamily. We also demonstrate that the substrate carboxylate group interacts with central residues of the basic ladder, a row of arginine and lysine residues that leads to and away from the binding site at the channel constriction. Moreover, the importance of the basic ladder residues corresponds to their degree of conservation. Finally, we apply the generated insights by converting the archetype of the entire family, OccD1, from a basic amino acid-specific channel into a channel with a preference for negatively charged amino acids.
引用
收藏
页码:12042 / 12053
页数:12
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