6of0

Structural basis for multidrug recognition and antimicrobial resistance by MTRR, an efflux pump regulator from Neisseria Gonorrhoeae

spinqualitylabelsall models 6of0, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6of0 is a 4 chain structure with sequence from Neisseria gonorrhoeae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2Å Ligands: PO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function MTRR_NEIGO Controls the permeability of the cell envelope to hydrophobic compounds such as antibiotics and detergents (PubMed:8196548). Represses transcription of the mtrCDE-encoded efflux pump by binding within the mtrCDE promoter (PubMed:9209024, PubMed:23221802). Also negatively regulates the expression of farR, by binding to its promoter region, leading indirectly to the positive regulation of expression of the farAB-encoded efflux pump (PubMed:14645274). Publication Abstract from PubMed Neisseria gonorrhoeae responds to host-derived antimicrobials by inducing the expression of the mtrCDE-encoded multidrug efflux pump, which expels microbicides such as bile salts, fatty acids, and multiple extrinsically administered drugs from the cell. In the absence of these cytotoxins, the TetR-family member, MtrR, represses the mtrCDE genes. Although antimicrobial-dependent derepression of mtrCDE is clear, the physiological inducers of MtrR are unknown. Here, we report the crystal structure of an induced form of MtrR. In the binding pocket of MtrR, we observe electron density that we hypothesize is cyclohexyl-3-aminopropanesulfonic acid (CAPS), a component of the crystallization reagent. Using the MtrR-CAPS structure as an inducer-bound template, we hypothesized that bile salts, which bear significant chemical resemblance to CAPS, are physiologically relevant inducers. Indeed, characterization of MtrR-chenodeoxycholate and MtrR-taurodeoxycholate interaction, both in vitro and in vivo, revealed these bile salts, but not glyocholate or taurocholate, bind MtrR tightly and can act as bona fide inducers. Furthermore, two residues, W136 and R176, were shown to be important in binding chenodeoxycholate, but not taurodeoxycholate, suggesting different binding modes of these bile salts. These data provide insight into a crucial mechanism utilized by this pathogen to overcome innate human defences.IMPORTANCE Neisseria gonorrhoeae causes significant disease burden worldwide and a meteoric rise in its multidrug resistance has reduced the efficacy of antibiotics previously or currently approved for therapy of gonorrheal infections. Multidrug efflux pump MtrCDE transports multiple drugs and host-derived antimicrobials from the bacterial cell and confers survival advantage to the pathogen within the host. Transcription of this pump is repressed by MtrR, but relieved by the cytosolic influx of antimicrobials. Here, we describe the structure of induced MtrR and use this structure to identify bile salts as physiological inducers of MtrR. These findings provide a mechanistic basis for antimicrobial sensing and gonococcal protection by MtrR through the derepression of mtrCDE expression after exposure to intrinsic and clinically applied antimicrobials. Structural, biochemical and in vivo characterization of MtrR-mediated resistance to innate antimicrobials by the human pathogen Neisseria gonorrhoeae.,Beggs GA, Zalucki YM, Brown NG, Rastegari S, Phillips RK, Palzkill T, Shafer W, Kumaraswami M, Brennan RG J Bacteriol. 2019 Jul 22. pii: JB.00401-19. doi: 10.1128/JB.00401-19. PMID:31331979 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Tetracycline repressor protein 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA