4bae: Difference between revisions

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-{{STRUCTURE_4bae|  PDB=4bae  |  SCENE=  }}
-===Optimisation of pyrroleamides as mycobacterial GyrB ATPase inhibitors: Structure Activity Relationship and in vivo efficacy in the mouse model of tuberculosis===
-{{ABSTRACT_PUBMED_24126580}}
-==Function==
+==Optimisation of pyrroleamides as mycobacterial GyrB ATPase inhibitors: Structure Activity Relationship and in vivo efficacy in the mouse model of tuberculosis==
-[[http://www.uniprot.org/uniprot/GYRB_MYCSM GYRB_MYCSM]] DNA gyrase negatively supercoils closed circular double-stranded DNA in an ATP-dependent manner and also catalyzes the interconversion of other topological isomers of double-stranded DNA rings, including catenanes and knotted rings.
+<StructureSection load='4bae' size='340' side='right'caption='[[4bae]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4bae]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycolicibacterium_smegmatis Mycolicibacterium smegmatis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BAE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BAE FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.35&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=RWX:2-[(3S,4R)-4-[(3-BROMANYL-4-CHLORANYL-5-METHYL-1H-PYRROL-2-YL)CARBONYLAMINO]-3-METHOXY-PIPERIDIN-1-YL]-4-(2-METHYL-1,2,4-TRIAZOL-3-YL)-1,3-THIAZOLE-5-CARBOXYLIC+ACID'>RWX</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4bae FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bae OCA], [https://pdbe.org/4bae PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bae RCSB], [https://www.ebi.ac.uk/pdbsum/4bae PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bae ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/GYRB_MYCSM GYRB_MYCSM] DNA gyrase negatively supercoils closed circular double-stranded DNA in an ATP-dependent manner and also catalyzes the interconversion of other topological isomers of double-stranded DNA rings, including catenanes and knotted rings.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Moxifloxacin has shown excellent activity against drug sensitive as well as drug resistant tuberculosis (TB) thus confirming DNA gyrase as a clinically validated target for discovering novel anti-TB agents. We have identified novel inhibitors in the pyrrolamide class which kill Mycobacterium tuberculosis through inhibition of ATPase activity catalysed by the GyrB domain of DNA gyrase. A homology model of M.tuberculosis H37Rv GyrB domain was used for deciphering structure activity relationship and binding interactions of inhibitors with mycobacterial GyrB enzyme. Proposed binding interactions were later confirmed through co-crystal structure studies with Mycobacterium smegmatis GyrB ATPase domain. The most potent compound in this series inhibited supercoiling activity of DNA gyrase with an IC50 &lt; 5 nM, an MIC of 0.03 mug/mL against M.tuberculosis H37Rv and an MIC90 &lt; 0.25 mug/mL against 99 drug resistant, clinical isolates of M.tuberculosis. The frequency of isolating spontaneous resistant mutants was approximately 10-6 to 10-8 and the point mutation mapped to M.tuberculosis GyrB domain (Ser 208 Ala) thus confirming its mode of action. The best compound tested for in vivo efficacy in the mouse model showed 1.1 log reduction in lung CFU in the acute model and 0.7 log reduction in the chronic model. This class of GyrB inhibitors could be developed as novel anti-TB agents.
-==About this Structure==
+Optimization of pyrrolamides as mycobacterial GyrB ATPase inhibitors: Structure Activity Relationship and in vivo efficacy in the mouse model of tuberculosis.,Hameed SP, Solapure S, Mukherjee K, Nandi V, Waterson D, Shandil R, Balganesh M, Sambandamurthy VK, Raichurkar AK, Deshpande A, Ghosh A, Awasthy D, Shanbhag G, Sheikh G, McMiken H, Puttur J, Reddy J, Werngren J, Read J, Kumar M, R M, Chinnapattu M, Madhavapeddi P, Manjrekar P, Basu R, Gaonkar S, Sharma S, Hoffner S, Humnabadkar V, Subbulakshmi V, Panduga V Antimicrob Agents Chemother. 2013 Oct 14. PMID:24126580<ref>PMID:24126580</ref>
-[[4bae]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Mycobacterium_smegmatis Mycobacterium smegmatis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BAE OCA].
-==Reference==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-<ref group="xtra">PMID:024126580</ref><references group="xtra"/><references/>
+</div>
-[[Category: Mycobacterium smegmatis]]
+<div class="pdbe-citations 4bae" style="background-color:#fffaf0;"></div>
-[[Category: Gingell, H G.]]
-[[Category: Madhavapeddi, P.]]
+==See Also==
-[[Category: Read, J A.]]
+*[[Gyrase 3D Structures|Gyrase 3D Structures]]
-[[Category: Dna topoisomerase]]
+== References ==
-[[Category: Inhibitor]]
+<references/>
-[[Category: Isomerase]]
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
+[[Category: Mycolicibacterium smegmatis]]
+[[Category: Gingell HG]]
+[[Category: Madhavapeddi P]]
+[[Category: Read JA]]