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Title | Structural analysis of phosphoribosyltransferase-mediated cell wall precursor synthesis in Mycobacterium tuberculosis. |
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Journal, issue, pages | Nat Microbiol, Vol. 9, Issue 4, Page 976-987, Year 2024 |
Publish date | Mar 15, 2024 |
Authors | Shan Gao / Fangyu Wu / Sudagar S Gurcha / Sarah M Batt / Gurdyal S Besra / Zihe Rao / Lu Zhang / |
PubMed Abstract | In Mycobacterium tuberculosis, Rv3806c is a membrane-bound phosphoribosyltransferase (PRTase) involved in cell wall precursor production. It catalyses pentosyl phosphate transfer from phosphoribosyl ...In Mycobacterium tuberculosis, Rv3806c is a membrane-bound phosphoribosyltransferase (PRTase) involved in cell wall precursor production. It catalyses pentosyl phosphate transfer from phosphoribosyl pyrophosphate to decaprenyl phosphate, to generate 5-phospho-β-ribosyl-1-phosphoryldecaprenol. Despite Rv3806c being an attractive drug target, structural and molecular mechanistic insight into this PRTase is lacking. Here we report cryogenic electron microscopy structures for Rv3806c in the donor- and acceptor-bound states. In a lipidic environment, Rv3806c is trimeric, creating a UbiA-like fold. Each protomer forms two helical bundles, which, alongside the bound lipids, are required for PRTase activity in vitro. Mutational and functional analyses reveal that decaprenyl phosphate and phosphoribosyl pyrophosphate bind the intramembrane and extramembrane cavities of Rv3806c, respectively, in a distinct manner to that of UbiA superfamily enzymes. Our data suggest a model for Rv3806c-catalysed phosphoribose transfer through an inverting mechanism. These findings provide a structural basis for cell wall precursor biosynthesis that could have potential for anti-tuberculosis drug development. |
External links | Nat Microbiol / PubMed:38491273 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.76 - 3.36 Å |
Structure data | EMDB-36071, PDB-8j8j: EMDB-36072, PDB-8j8k: |
Chemicals | ChemComp-PRP: ChemComp-MG: ChemComp-PGW: ChemComp-DSL: |
Source |
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Keywords | MEMBRANE PROTEIN / phosphoribose transferase complex |