1zau
From Proteopedia
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[[Image:1zau.gif|left|200px]] | [[Image:1zau.gif|left|200px]] | ||
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'''Adenylation domain of NAD+ dependent DNA ligase from M.tuberculosis''' | '''Adenylation domain of NAD+ dependent DNA ligase from M.tuberculosis''' | ||
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==Reference== | ==Reference== | ||
NAD+-dependent DNA Ligase (Rv3014c) from Mycobacterium tuberculosis. Crystal structure of the adenylation domain and identification of novel inhibitors., Srivastava SK, Tripathi RP, Ramachandran R, J Biol Chem. 2005 Aug 26;280(34):30273-81. Epub 2005 May 17. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15901723 15901723] | NAD+-dependent DNA Ligase (Rv3014c) from Mycobacterium tuberculosis. Crystal structure of the adenylation domain and identification of novel inhibitors., Srivastava SK, Tripathi RP, Ramachandran R, J Biol Chem. 2005 Aug 26;280(34):30273-81. Epub 2005 May 17. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15901723 15901723] | ||
| - | [[Category: DNA ligase (NAD(+))]] | ||
[[Category: Mycobacterium tuberculosis]] | [[Category: Mycobacterium tuberculosis]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Ramachandran, R.]] | [[Category: Ramachandran, R.]] | ||
[[Category: Srivastava, S K.]] | [[Category: Srivastava, S K.]] | ||
| - | [[Category: | + | [[Category: Amp]] |
| - | [[Category: | + | [[Category: M tuberculosis]] |
| - | [[Category: | + | [[Category: Nad+ dependent dna ligase]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 17:24:01 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 14:24, 3 May 2008
Adenylation domain of NAD+ dependent DNA ligase from M.tuberculosis
Overview
DNA ligases utilize either ATP or NAD+ as cofactors to catalyze the formation of phosphodiester bonds in nicked DNA. Those utilizing NAD+ are attractive drug targets because of the unique cofactor requirement for ligase activity. We report here the crystal structure of the adenylation domain of the Mycobacterium tuberculosis NAD+-dependent ligase with bound AMP. The adenosine nucleoside moiety of AMP adopts a syn-conformation. The structure also captures a new spatial disposition between the two subdomains of the adenylation domain. Based on the crystal structure and an in-house compound library, we have identified a novel class of inhibitors for the enzyme using in silico docking calculations. The glycosyl ureide-based inhibitors were able to distinguish between NAD+- and ATP-dependent ligases as evidenced by in vitro assays using T4 ligase and human DNA ligase I. Moreover, assays involving an Escherichia coli strain harboring a temperature-sensitive ligase mutant and a ligase-deficient Salmonella typhimurium strain suggested that the bactericidal activity of the inhibitors is due to inhibition of the essential ligase enzyme. The results can be used as the basis for rational design of novel antibacterial agents.
About this Structure
1ZAU is a Single protein structure of sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA.
Reference
NAD+-dependent DNA Ligase (Rv3014c) from Mycobacterium tuberculosis. Crystal structure of the adenylation domain and identification of novel inhibitors., Srivastava SK, Tripathi RP, Ramachandran R, J Biol Chem. 2005 Aug 26;280(34):30273-81. Epub 2005 May 17. PMID:15901723 Page seeded by OCA on Sat May 3 17:24:01 2008
