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1zau

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[[Image:1zau.gif|left|200px]]<br /><applet load="1zau" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1zau, resolution 3.15&Aring;" />
 
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'''Adenylation domain of NAD+ dependent DNA ligase from M.tuberculosis'''<br />
 
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==Overview==
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==Adenylation domain of NAD+ dependent DNA ligase from M.tuberculosis==
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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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<StructureSection load='1zau' size='340' side='right'caption='[[1zau]], [[Resolution|resolution]] 3.15&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1zau]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ZAU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1ZAU FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.15&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AMP:ADENOSINE+MONOPHOSPHATE'>AMP</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1zau FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1zau OCA], [https://pdbe.org/1zau PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1zau RCSB], [https://www.ebi.ac.uk/pdbsum/1zau PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1zau ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/DNLJ_MYCTU DNLJ_MYCTU] DNA ligase that catalyzes the formation of phosphodiester linkages between 5'-phosphoryl and 3'-hydroxyl groups in double-stranded DNA using NAD as a coenzyme and as the energy source for the reaction. It is essential for DNA replication and repair of damaged DNA.[HAMAP-Rule:MF_01588]
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/za/1zau_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1zau ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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1ZAU is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis] with <scene name='pdbligand=AMP:'>AMP</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/DNA_ligase_(NAD(+)) DNA ligase (NAD(+))], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.5.1.2 6.5.1.2] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ZAU OCA].
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*[[DNA ligase 3D structures|DNA ligase 3D structures]]
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__TOC__
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==Reference==
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</StructureSection>
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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://ispc.weizmann.ac.il//pmbin/getpm?pmid=15901723 15901723]
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[[Category: Large Structures]]
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[[Category: DNA ligase (NAD(+))]]
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[[Category: Mycobacterium tuberculosis]]
[[Category: Mycobacterium tuberculosis]]
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[[Category: Single protein]]
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[[Category: Ramachandran R]]
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[[Category: Ramachandran, R.]]
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[[Category: Srivastava SK]]
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[[Category: Srivastava, S K.]]
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[[Category: AMP]]
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[[Category: amp]]
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[[Category: m tuberculosis]]
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[[Category: nad+ dependent dna ligase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:13:49 2008''
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Current revision

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

PDB ID 1zau

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