6d4t: Difference between revisions
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==M. thermoresistible GuaB2 delta-CBS in complex with inhibitor Compound 45 (VCC117054)== | |||
<StructureSection load='6d4t' size='340' side='right'caption='[[6d4t]], [[Resolution|resolution]] 1.54Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6d4t]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycolicibacterium_thermoresistibile_ATCC_19527 Mycolicibacterium thermoresistibile ATCC 19527]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6D4T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6D4T 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]] 1.54Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FWS:(2S)-N-(2H-1,3-benzodioxol-5-yl)-4-[(isoquinolin-5-yl)sulfonyl]-2-methylpiperazine-1-carboxamide'>FWS</scene>, <scene name='pdbligand=IMP:INOSINIC+ACID'>IMP</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=6d4t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d4t OCA], [https://pdbe.org/6d4t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6d4t RCSB], [https://www.ebi.ac.uk/pdbsum/6d4t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6d4t ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/G7CNL4_MYCT3 G7CNL4_MYCT3] Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth.[HAMAP-Rule:MF_01964] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Tuberculosis (TB) is a major infectious disease associated increasingly with drug resistance. Thus, new anti-tubercular agents with novel mechanisms of action are urgently required for the treatment of drug-resistant TB. In prior work, we identified compound 1 (cyclohexyl(4-(isoquinolin-5-ylsulfonyl)piperazin-1-yl)methanone) and showed that its anti-tubercular activity is attributable to inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH) in Mycobacterium tuberculosis. In the present study, we explored the structure-activity relationship around compound 1 by synthesizing and evaluating the inhibitory activity of analogues against M. tuberculosis IMPDH in biochemical and whole-cell assays. X-ray crystallography was performed to elucidate the mode of binding of selected analogues to IMPDH. We establish the importance of the cyclohexyl, piperazine and isoquinoline rings for activity, and report the identification of an analogue with IMPDH-selective activity against a mutant of M. tuberculosis that is highly resistant to compound 1. We also show that the nitrogen in urea analogues is required for anti-tubercular activity and identify benzylurea derivatives as promising inhibitors that warrant further investigation. | |||
Synthesis and Structure-Activity relationship of 1-(5-isoquinolinesulfonyl)piperazine analogues as inhibitors of Mycobacterium tuberculosis IMPDH.,Singh V, Pacitto A, Donini S, Ferraris DM, Boros S, Illyes E, Szokol B, Rizzi M, Blundell TL, Ascher DB, Pato J, Mizrahi V Eur J Med Chem. 2019 Jul 15;174:309-329. doi: 10.1016/j.ejmech.2019.04.027. Epub , 2019 Apr 15. PMID:31055147<ref>PMID:31055147</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6d4t" style="background-color:#fffaf0;"></div> | ||
[[Category: Ascher | |||
[[Category: Pacitto | ==See Also== | ||
*[[Inosine monophosphate dehydrogenase 3D structures|Inosine monophosphate dehydrogenase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mycolicibacterium thermoresistibile ATCC 19527]] | |||
[[Category: Ascher DB]] | |||
[[Category: Blundell TL]] | |||
[[Category: Pacitto A]] | |||
Latest revision as of 18:18, 4 October 2023
M. thermoresistible GuaB2 delta-CBS in complex with inhibitor Compound 45 (VCC117054)M. thermoresistible GuaB2 delta-CBS in complex with inhibitor Compound 45 (VCC117054)
Structural highlights
FunctionG7CNL4_MYCT3 Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth.[HAMAP-Rule:MF_01964] Publication Abstract from PubMedTuberculosis (TB) is a major infectious disease associated increasingly with drug resistance. Thus, new anti-tubercular agents with novel mechanisms of action are urgently required for the treatment of drug-resistant TB. In prior work, we identified compound 1 (cyclohexyl(4-(isoquinolin-5-ylsulfonyl)piperazin-1-yl)methanone) and showed that its anti-tubercular activity is attributable to inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH) in Mycobacterium tuberculosis. In the present study, we explored the structure-activity relationship around compound 1 by synthesizing and evaluating the inhibitory activity of analogues against M. tuberculosis IMPDH in biochemical and whole-cell assays. X-ray crystallography was performed to elucidate the mode of binding of selected analogues to IMPDH. We establish the importance of the cyclohexyl, piperazine and isoquinoline rings for activity, and report the identification of an analogue with IMPDH-selective activity against a mutant of M. tuberculosis that is highly resistant to compound 1. We also show that the nitrogen in urea analogues is required for anti-tubercular activity and identify benzylurea derivatives as promising inhibitors that warrant further investigation. Synthesis and Structure-Activity relationship of 1-(5-isoquinolinesulfonyl)piperazine analogues as inhibitors of Mycobacterium tuberculosis IMPDH.,Singh V, Pacitto A, Donini S, Ferraris DM, Boros S, Illyes E, Szokol B, Rizzi M, Blundell TL, Ascher DB, Pato J, Mizrahi V Eur J Med Chem. 2019 Jul 15;174:309-329. doi: 10.1016/j.ejmech.2019.04.027. Epub , 2019 Apr 15. PMID:31055147[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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