1zau

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{{STRUCTURE_1zau| PDB=1zau | SCENE= }}
{{STRUCTURE_1zau| PDB=1zau | SCENE= }}
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'''Adenylation domain of NAD+ dependent DNA ligase from M.tuberculosis'''
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===Adenylation domain of NAD+ dependent DNA ligase from M.tuberculosis===
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==Overview==
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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.
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{{ABSTRACT_PUBMED_15901723}}
==About this Structure==
==About this Structure==
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[[Category: M tuberculosis]]
[[Category: M tuberculosis]]
[[Category: Nad+ dependent dna ligase]]
[[Category: Nad+ dependent dna ligase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 17:24:01 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 12:33:09 2008''

Revision as of 09:33, 28 July 2008

Image:1zau.png

Template:STRUCTURE 1zau

Adenylation domain of NAD+ dependent DNA ligase from M.tuberculosis

Template:ABSTRACT PUBMED 15901723

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

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