The TB Structural Genomics Consortium: A decade of progress

Chim, Nicholas; Habel, J.; Johnston, Jodie M.; Krieger, I.V.; Miallau, L.; Sankaranarayanan, R.; Morse, Robert P.; Bruning, John B.; Swanson, Scott R.; Kim, Haelee; Kim, Chang-Yub; Li, Hongye; Bulloch, Esther M. M.; Payne, Richard J.; Manos-Turvey, Alexandra; Hung, Li Wei; Baker, Edward N.; Lott, J.S.; James, Michael N.G.; Terwilliger, Thomas C.; Eisenberg, David; Sacchettini, James C.; Goulding, Celia W.

doi:10.1016/j.tube.2010.11.009

Cited by 42 publications

(44 citation statements)

References 152 publications

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“…Under normal physiological conditions both proteins are expressed and form a tight complex. However, under conditions of stress such as viral invasion, oxidative stress, or antibiotic attack, the unstable antitoxin is rapidly degraded by proteases, and thus the toxin is free to kill the host cell (13). The number of such TA systems in mycobacteria is high, and estimates range from 90 to over 120 genes.…”

Section: Insights Into Two-component Systemsmentioning

confidence: 99%

“…Efforts from such a consortium of several investigators across the globe, along with other TB structural projects, have led to the elucidation of structural information for about 10% of the proteome. The TBSGC has contributed 724 structures from 266 unique open reading frames to date, accounting for one-third of M. tuberculosis protein structures in the Protein Data Bank (PDB) (13). Although tremendous advances have been made in experimental methods to determine protein structure on a high-throughput scale, some bottlenecks still persist.…”

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confidence: 99%

“…This approach has been utilized to obtain structural information for nearly 70% of the proteome (17). There are already a few excellent review articles on the structural biology of M. tuberculosis describing structural details of proteins involved in important biological processes (12,13,18,19). This chapter focuses on a structural view of the entire proteome and the functional inferences obtained through this knowledge.…”

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confidence: 99%

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Structural Annotation of the Mycobacterium tuberculosis Proteome

Chandra

Sandhya

2014

Microbiol Spectr

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Efforts from the TB Structural Genomics Consortium together with those of tuberculosis structural biologists worldwide have led to the determination of about 350 structures, making up nearly a tenth of the pathogen's proteome. Given that knowledge of protein structures is essential to obtaining a high-resolution understanding of the underlying biology, it is desirable to have a structural view of the entire proteome. Indeed, structure prediction methods have advanced sufficiently to allow structural models of many more proteins to be built based on homology modeling and fold recognition strategies. By means of these approaches, structural models for about 2,877 proteins, making up nearly 70% of the Mycobacterium tuberculosis proteome, are available. Knowledge from bioinformatics has made significant inroads into an improved annotation of the M. tuberculosis genome and in the prediction of key protein players that interact in vital pathways, some of which are unique to the organism. Functional inferences have been made for a large number of proteins based on fold-function associations. More importantly, ligand-binding pockets of the proteins are identified and scanned against a large database, leading to binding site–based ligand associations and hence structure-based function annotation. Near proteome-wide structural models provide a global perspective of the fold distribution in the genome. New insights about the folds that predominate in the genome, as well as the fold combinations that make up multidomain proteins, are also obtained. This chapter describes the structural proteome, functional inferences drawn from it, and its applications in drug discovery.

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Section: Insights Into Two-component Systemsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Structural Annotation of the Mycobacterium tuberculosis Proteome

Chandra

Sandhya

2014

Microbiol Spectr

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“…Thanks to the efforts of the Tuberculosis Structural Genomics, more than 260 X-ray crystal structures of interesting proteins have been completed (Chim et al, 2011). The availability of these structures provides the opportunity to carry out virtual screenings for drug discovery.…”

Section: Introductionmentioning

confidence: 99%

Fighting Against Resistant Strains: The Case of Benzothiazinones and Dinitrobenzamides

Buroni¹,

Riccardi²,

Pasca³

2012

Understanding Tuberculosis - New Approaches to Fighting Against Drug Resistance

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“…Another approach is to target the disulfide pathways that mediate disulfide-bond formation and correct folding of exported proteins in Mtb (Chim et al, 2010(Chim et al, , 2011Goulding et al, 2004). In bacteria, disulfide-bond formation in newly exported proteins is commonly mediated through mechanisms that rely on electron transfer between redox proteins.…”

Section: Discussionmentioning

confidence: 99%

Design, synthesis and evaluation of peptides and peptidomimetics inhibiting the bacterial DsbA-DsbB interaction

Duprez¹

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The rapid development and dissemination of antibiotic resistance in pathogenic bacteria requires new strategies and new structural scaffolds of antimicrobial compounds to be investigated. A developing trend targets virulence factors rather than pathways essential for survival in an effort to neutralize pathogens while minimizing the risk of resistance. The thesis focuses on the design of new molecules from peptides to peptidomimetics aimed at disrupting the bacterial periplasmic oxidative system, a new antivirulence target.This thesis initially describes in chapter I the recent emergence of peptidomimetics in antimicrobial treatments aimed at well-known mechanisms as well as novel targets.Peptidomimetics may be particularly efficient for disrupting protein-protein interactions and have been successful for instance in preventing post-translational modifications or the formation of pili machinery. The thesis also highlights the mechanism and context of the interaction between DsbA and DsbB, both primary factors in the periplasmic oxidative system of gram-negative bacteria and the target proteins of this PhD.Developing inhibitors requires a solid screening pipeline of biophysical assays to measure binding parameters such as affinity, thermodynamics and kinetics. Chapter II highlights the building and optimization of such a pipeline by evaluating differential scanning fluorimetry, isothermal titration calorimetry, surface plasmon resonance, substrate oxidation assay and crystallography in order to characterize the designed peptide scaffolds.Chapter III focuses on the structure-activity relationship studies of 31 manually synthesized peptide sequences screened through this pipeline. Based on peptide length scouting, alanine scanning and rational substitution of specific residues, a final heptameric peptide was found to bind Escherichia coli DsbA with a Kd of 2.9 ± 0.3 µM. Moreover, the data suggest a probable disulfide bond formation between peptide and DsbA essential to the binding interface, while cysteine-free peptides present very weak affinity towards EcDsbA. This chapter generated a manuscript submitted to the Journal of Medicinal Chemistry.iiiIn a slightly different strategy, Chapter IV evaluates this best heptamer peptide sequence against a newly characterized Proteus Mirabilis DsbA, a structurally related protein (59% similarity with E. coli DsbA) showing promise for co-crystallization. With the peptide showing the same affinity against wild type E. coli and P. mirabilis DsbA, a highresolution (1.6 Å) co-crystal structure of the heptamer peptide bound to a cysteine mutant of P. mirabilis DsbA was solved. This structure shows the peptide binding to the P.mirabilis DsbA active site in a similar fashion to the native E. coli DsbA/DsbB interaction and differently from E. coli DsbA substrates. In-depth analysis of the high-resolution structure identifies two binding anchors, a H-bond-rich region and a hydrophobic pocket, which can be optimized for tighter affinities. This chapter generated a manuscript su...

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The TB Structural Genomics Consortium: A decade of progress

Cited by 42 publications

References 152 publications

Structural Annotation of the Mycobacterium tuberculosis Proteome

Structural Annotation of the Mycobacterium tuberculosis Proteome

Fighting Against Resistant Strains: The Case of Benzothiazinones and Dinitrobenzamides

Design, synthesis and evaluation of peptides and peptidomimetics inhibiting the bacterial DsbA-DsbB interaction

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