Allosteric inhibitors of Mycobacterium tuberculosis tryptophan synthase.
Mycobacterium tuberculosis
allosteric regulation
catalysis
crystal structure
enzyme inhibitor
tryptophan
tryptophan synthase
tuberculosis
Journal
Protein science : a publication of the Protein Society
ISSN: 1469-896X
Titre abrégé: Protein Sci
Pays: United States
ID NLM: 9211750
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
30
10
2019
revised:
07
01
2020
accepted:
08
01
2020
pubmed:
14
1
2020
medline:
3
2
2021
entrez:
14
1
2020
Statut:
ppublish
Résumé
Global dispersion of multidrug resistant bacteria is very common and evolution of antibiotic-resistance is occurring at an alarming rate, presenting a formidable challenge for humanity. The development of new therapeuthics with novel molecular targets is urgently needed. Current drugs primarily affect protein, nucleic acid, and cell wall synthesis. Metabolic pathways, including those involved in amino acid biosynthesis, have recently sparked interest in the drug discovery community as potential reservoirs of such novel targets. Tryptophan biosynthesis, utilized by bacteria but absent in humans, represents one of the currently studied processes with a therapeutic focus. It has been shown that tryptophan synthase (TrpAB) is required for survival of Mycobacterium tuberculosis in macrophages and for evading host defense, and therefore is a promising drug target. Here we present crystal structures of TrpAB with two allosteric inhibitors of M. tuberculosis tryptophan synthase that belong to sulfolane and indole-5-sulfonamide chemical scaffolds. We compare our results with previously reported structural and biochemical studies of another, azetidine-containing M. tuberculosis tryptophan synthase inhibitor. This work shows how structurally distinct ligands can occupy the same allosteric site and make specific interactions. It also highlights the potential benefit of targeting more variable allosteric sites of important metabolic enzymes.
Identifiants
pubmed: 31930594
doi: 10.1002/pro.3825
pmc: PMC7020977
doi:
Substances chimiques
Enzyme Inhibitors
0
Indoles
0
Ligands
0
Sulfonamides
0
Thiophenes
0
Tryptophan Synthase
EC 4.2.1.20
sulfolane
Y5L06AH4G5
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
779-788Subventions
Organisme : NIGMS NIH HHS
ID : R24 GM115586
Pays : United States
Organisme : NIH HHS
ID : HHSN272201200026C
Pays : United States
Organisme : NIH HHS
ID : GM115586
Pays : United States
Organisme : NIH HHS
ID : HHSN272201700060C
Pays : United States
Organisme : NIAID NIH HHS
ID : HHSN272201700060C
Pays : United States
Organisme : NIAID NIH HHS
ID : HHSN272201200026C
Pays : United States
Informations de copyright
© 2020 The Protein Society.
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