The Structure and Interactions of Periplasmic Domains of Crucial MmpL Membrane Proteins from Mycobacterium tuberculosis

Chim, Nicholas; Torres, Rodrigo; Liu, Yuqi; Capri, Joseph; Batot, Gaëlle; Whitelegge, Julian P.; Goulding, Celia W.

doi:10.1016/j.chembiol.2015.07.013

Cited by 46 publications

(69 citation statements)

References 51 publications

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“…The modeled structures of the MmpL3 PN and PC periplasmic regions were structurally similar and superimposed with an RMS = 3.05Å, while the structure of the equivalent MmpL11 PC fragment (PDB ID: 4Y0L), 6 homologous to the MmpL3 PC region, displayed the same topological fold as those predicted for the PN and PC regions of our model. The helical axis of TMS-11 is approximately parallel to the 3-fold axis of the MmpL3 trimer [Fig.…”

Section: Resultssupporting

confidence: 55%

Structure–Function Profile of MmpL3, the Essential Mycolic Acid Transporter from Mycobacterium tuberculosis

et al. 2016

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The MmpL family of proteins translocates complex (glyco)lipids and siderophores across the cell envelope of mycobacteria and closely related Corynebacteriaceae, and plays important roles in the biogenesis of the outer membrane of these organisms. Despite their significance in the physiology and virulence of Mycobacterium tuberculosis, and from the perspective of developing novel antituberculosis agents, little is known about their structure and mechanism of translocation. In this study, the essential mycobacterial mycolic acid transporter, MmpL3, and its ortholog in Corynebacterium glutamicum, CmpL1, were investigated as prototypical MmpL proteins to gain insight into the transmembrane topology, tertiary and quaternary structures, and functional regions of this transporter family. Our combined genetic, biochemical and biophysical studies indicate that MmpL3 and CmpL1 are structurally similar to Gram-negative Resistance-Nodulation and Division efflux pumps. They harbor twelve transmembrane segments interrupted by two large soluble periplasmic domains, and function as homotrimers to export long-chain (C22-C90) mycolic acids, possibly in their acetylated form, esterified to trehalose. The mapping of a number of functional residues within the middle region of the transmembrane domain of MmpL3 shows a striking overlap with mutations associated with resistance to MmpL3 inhibitors. Our results suggest that structurally diverse inhibitors of MmpL3 all target the proton translocation path of the transporter and that multi-resistance to these inhibitors is enabled by conformational changes in MmpL3.

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Section: Resultssupporting

confidence: 55%

Structure–Function Profile of MmpL3, the Essential Mycolic Acid Transporter from Mycobacterium tuberculosis

et al. 2016

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“…These two domains are separated by a single cytoplasmic helix between TM6 and TM7 that is orientated in parallel to the plasma membrane, in agreement with other RND protein structures. Additionally, two periplasmic domains, designated the porter domains, are located between TM1 and TM2 and between TM7 and TM8 respectively (Chim et al ., ). Chim et al .…”

Section: Introductionmentioning

confidence: 97%

“…The genome of Mycobacterium tuberculosis encodes 14 annotated MmpL proteins (Cole et al ., ) whereas the genome of Corynebacterium glutamicum encodes only four MmpL‐like transporters, designated CmpL (Yang et al ., ). Consistent with other RND proteins, such as the well‐characterised multidrug efflux pump AcrB, the active component of the major efflux system AcrAB‐TolC of Escherichia coli (Nikaido and Takatsuka, ; Eicher et al ., ), the MmpL/CmpL transporters require the inner membrane electrochemical proton gradient for activity as well as predicted topological features (Tseng et al ., ; Yang et al ., ; Li et al ., ; Chim et al ., ; Bernut et al ., ). However, unlike the AcrAB‐TolC system that mediates the efflux of exogenous compounds, the MmpL/CmpL proteins essentially appear to export endogenous lipophilic molecules with a relatively narrow substrate specificity (Székely and Cole, ; Chalut, ).…”

Section: Introductionmentioning

confidence: 99%

The diverse family of MmpL transporters in mycobacteria: from regulation to antimicrobial developments

Viljoen

Dubois

Girard-Misguich

et al. 2017

Molecular Microbiology

114

119

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SummaryMycobacterial genomes contain large sets of loci encoding membrane proteins that belong to a family of multidrug resistance pumps designated Resistance-Nodulation-Cell Division (RND) permeases. Mycobacterial membrane protein Large (MmpL) transporters represent a subclass of RND transporters known to participate in the export of lipid components across the cell envelope. These surfaceexposed lipids with unusual structures play key roles in the physiology of mycobacteria and/or can act as virulence factors and immunomodulators. Defining the substrate specificity of MmpLs and their mechanisms of regulation helps understanding how mycobacteria elaborate their complex cell wall. This review describes the diversity of MmpL proteins in mycobacteria, emphasising their high abundance in a few opportunistic rapid-growing mycobacteria. It reports the conservation of mmpL loci between Mycobacterium tuberculosis and non-tuberculous mycobacteria, useful in predicting the role of MmpLs with unknown functions. Paradoxically, whereas MmpLs participate in drug resistance mechanisms, they represent also attractive pharmacological targets, opening the way for exciting translational applications. The most recent advances regarding structural/ functional information are also provided to explain the molecular basis underlying the proton-motive force driven lipid transport. Overall, this review emphasises the Janus-face nature of MmpLs at the crossroads between antibiotic resistance mechanisms and exquisite vulnerability to drugs.

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“…These proteins export mycolic acids bound to arabinogalactan and trehalose monomycolate for the synthesis of trehalose dimycolate . The necessity of MmpL3 for the viability of M. tuberculosis has made it a successful target in the last decade . There are 13 MmpL proteins encoded in M. tuberculosis .…”

Section: Sq109mentioning

confidence: 99%

An overview of new antitubercular drugs, drug candidates, and their targets

Bahuguna

Rawat

2019

Medicinal Research Reviews

131

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The causative agent of tuberculosis (TB), Mycobacterium tuberculosis and more recently totally drug‐resistant strains of M. tuberculosis, display unique mechanisms to survive in the host. A four‐drug treatment regimen was introduced 40 years ago but the emergence of multidrug‐resistance and more recently TDR necessitates the identification of new targets and drugs for the cure of M. tuberculosis infection. The current efforts in the drug development process are insufficient to completely eradicate the TB epidemic. For almost five decades the TB drug development process remained stagnant. The last 10 years have made sudden progress giving some new and highly promising drugs including bedaquiline, delamanid, and pretomanid. Many of the candidates are repurposed compounds, which were developed to treat other infections but later, exhibited anti‐TB properties also. Each class of drug has a specific target and a definite mode of action. These targets are either involved in cell wall biosynthesis, protein synthesis, DNA/RNA synthesis, or metabolism. This review discusses recent progress in the discovery of newly developed and Food and Drug Administration approved drugs as well as repurposed drugs, their targets, mode of action, drug‐target interactions, and their structure‐activity relationship.

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The Structure and Interactions of Periplasmic Domains of Crucial MmpL Membrane Proteins from Mycobacterium tuberculosis

Cited by 46 publications

References 51 publications

Structure–Function Profile of MmpL3, the Essential Mycolic Acid Transporter from Mycobacterium tuberculosis

Structure–Function Profile of MmpL3, the Essential Mycolic Acid Transporter from Mycobacterium tuberculosis

The diverse family of MmpL transporters in mycobacteria: from regulation to antimicrobial developments

An overview of new antitubercular drugs, drug candidates, and their targets

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