4lh6: Difference between revisions
Jump to navigation
Jump to search
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Crystal structure of a LigA inhibitor== | |||
=== | <StructureSection load='4lh6' size='340' side='right' caption='[[4lh6]], [[Resolution|resolution]] 1.65Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4lh6]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Entfa Entfa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LH6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LH6 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1X7:4-AMINO-2-BROMOTHIENO[3,2-C]PYRIDINE-7-CARBOXAMIDE'>1X7</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NMN:BETA-NICOTINAMIDE+RIBOSE+MONOPHOSPHATE'>NMN</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4lh7|4lh7]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ligA, EF_0722 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=226185 ENTFA])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4lh6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lh6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4lh6 RCSB], [http://www.ebi.ac.uk/pdbsum/4lh6 PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
In an attempt to identify novel inhibitors of NAD+-dependent DNA ligase (LigA) that are not affected by a known resistance mutation in the adenosine binding pocket, a detailed analysis of the binding sites of a variety of bacterial ligases was performed. This analysis revealed several similarities to the adenine binding region of kinases, which enabled a virtual screen of known kinase inhibitors. From this screen, a thienopyridine scaffold was identified that was shown to inhibit bacterial ligase. Further characterization through structure and enzymology revealed the compound was not affected by a previously disclosed resistance mutation in Streptococcus pneumoniae LigA, Leu75Phe. A subsequent medicinal chemistry program identified substitutions that resulted in an inhibitor with moderate activity across various Gram-positive bacterial LigA enzymes. | |||
Identification through structure-based methods of a bacterial NAD-dependent DNA ligase inhibitor that avoids known resistance mutations.,Murphy-Benenato K, Wang H, McGuire HM, Davis HE, Gao N, Prince DB, Jahic H, Stokes SS, Boriack-Sjodin PA Bioorg Med Chem Lett. 2013 Nov 15. pii: S0960-894X(13)01286-9. doi:, 10.1016/j.bmcl.2013.11.007. PMID:24287382<ref>PMID:24287382</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== | ==See Also== | ||
*[[DNA ligase|DNA ligase]] | |||
[[Category: Benenato, K | == References == | ||
[[Category: Boriack-Sjodin, P A | <references/> | ||
[[Category: Davis, H | __TOC__ | ||
[[Category: Gao, N | </StructureSection> | ||
[[Category: Jahic, H | [[Category: Entfa]] | ||
[[Category: Mcguire, H M | [[Category: Benenato, K]] | ||
[[Category: Prince, D B | [[Category: Boriack-Sjodin, P A]] | ||
[[Category: Stokes, S S | [[Category: Davis, H]] | ||
[[Category: Wang, H | [[Category: Gao, N]] | ||
[[Category: Jahic, H]] | |||
[[Category: Mcguire, H M]] | |||
[[Category: Prince, D B]] | |||
[[Category: Stokes, S S]] | |||
[[Category: Wang, H]] | |||
[[Category: Ligase-ligase inhibitor complex]] | [[Category: Ligase-ligase inhibitor complex]] | ||
[[Category: Protein-inhibitor complex]] | [[Category: Protein-inhibitor complex]] | ||
Revision as of 21:38, 21 December 2014
Crystal structure of a LigA inhibitorCrystal structure of a LigA inhibitor
Structural highlights
Publication Abstract from PubMedIn an attempt to identify novel inhibitors of NAD+-dependent DNA ligase (LigA) that are not affected by a known resistance mutation in the adenosine binding pocket, a detailed analysis of the binding sites of a variety of bacterial ligases was performed. This analysis revealed several similarities to the adenine binding region of kinases, which enabled a virtual screen of known kinase inhibitors. From this screen, a thienopyridine scaffold was identified that was shown to inhibit bacterial ligase. Further characterization through structure and enzymology revealed the compound was not affected by a previously disclosed resistance mutation in Streptococcus pneumoniae LigA, Leu75Phe. A subsequent medicinal chemistry program identified substitutions that resulted in an inhibitor with moderate activity across various Gram-positive bacterial LigA enzymes. Identification through structure-based methods of a bacterial NAD-dependent DNA ligase inhibitor that avoids known resistance mutations.,Murphy-Benenato K, Wang H, McGuire HM, Davis HE, Gao N, Prince DB, Jahic H, Stokes SS, Boriack-Sjodin PA Bioorg Med Chem Lett. 2013 Nov 15. pii: S0960-894X(13)01286-9. doi:, 10.1016/j.bmcl.2013.11.007. PMID:24287382[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||||||