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6d4s

From Proteopedia

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Current revision

M. thermoresistible GuaB2 delta-CBS in complex with inhibitor Compound 37 (VCC670597)

Structural highlights

6d4s is a 1 chain structure with sequence from Mycolicibacterium thermoresistibile ATCC 19527. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.63Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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]

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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Singh V, Pacitto A, Donini S, Ferraris DM, Boros S, Illyes E, Szokol B, Rizzi M, Blundell TL, Ascher DB, Pato J, Mizrahi V. Synthesis and Structure-Activity relationship of 1-(5-isoquinolinesulfonyl)piperazine analogues as inhibitors of Mycobacterium tuberculosis IMPDH. Eur J Med Chem. 2019 Jul 15;174:309-329. doi: 10.1016/j.ejmech.2019.04.027. Epub , 2019 Apr 15. PMID:31055147 doi:http://dx.doi.org/10.1016/j.ejmech.2019.04.027

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6d4s"

Categories: Large Structures | Mycolicibacterium thermoresistibile ATCC 19527 | Ascher DB | Blundell TL | Pacitto A

@@ Line 3: / Line 3: @@
 <StructureSection load='6d4s' size='340' side='right'caption='[[6d4s]], [[Resolution|resolution]] 1.63&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6d4s]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Myct3 Myct3]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6D4S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6D4S FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6d4s]] 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=6D4S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6D4S FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FWV:N-(2,3-dichlorophenyl)-4-[(isoquinolin-5-yl)sulfonyl]piperazine-1-carboxamide'>FWV</scene>, <scene name='pdbligand=IMP:INOSINIC+ACID'>IMP</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.63&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">guaB, KEK_23061 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1078020 MYCT3])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FWV:N-(2,3-dichlorophenyl)-4-[(isoquinolin-5-yl)sulfonyl]piperazine-1-carboxamide'>FWV</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6d4s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d4s OCA], [http://pdbe.org/6d4s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6d4s RCSB], [http://www.ebi.ac.uk/pdbsum/6d4s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6d4s ProSAT]</span></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=6d4s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d4s OCA], [https://pdbe.org/6d4s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6d4s RCSB], [https://www.ebi.ac.uk/pdbsum/6d4s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6d4s ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://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]
+[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 ==
@@ Line 27: / Line 27: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Myct3]]
+[[Category: Mycolicibacterium thermoresistibile ATCC 19527]]
-[[Category: Ascher, D B]]
+[[Category: Ascher DB]]
-[[Category: Blundell, T L]]
+[[Category: Blundell TL]]
-[[Category: Pacitto, A]]
+[[Category: Pacitto A]]
-[[Category: Complex]]
-[[Category: Fragment]]
-[[Category: Impdh]]
-[[Category: Oxidoreductase]]
-[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]

6d4s

From Proteopedia

Current revision

M. thermoresistible GuaB2 delta-CBS in complex with inhibitor Compound 37 (VCC670597)

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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