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< | ==Second-generation sulfonamide inhibitors of MurD: Activity optimisation with conformationally rigid analogues of D-glutamic acid== | ||
<StructureSection load='2xpc' size='340' side='right'caption='[[2xpc]], [[Resolution|resolution]] 1.49Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2xpc]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2XPC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2XPC FirstGlance]. <br> | |||
or | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.49Å</td></tr> | ||
-- | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=051:(1R,3R,4S)-4-[({6-[(4-CYANO-2-FLUOROBENZYL)OXY]NAPHTHALEN-2-YL}SULFONYL)AMINO]CYCLOHEXANE-1,3-DICARBOXYLIC+ACID'>051</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=KCX:LYSINE+NZ-CARBOXYLIC+ACID'>KCX</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=2xpc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xpc OCA], [https://pdbe.org/2xpc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2xpc RCSB], [https://www.ebi.ac.uk/pdbsum/2xpc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2xpc ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/MURD_ECOLI MURD_ECOLI] Cell wall formation. Catalyzes the addition of glutamate to the nucleotide precursor UDP-N-acetylmuramoyl-L-alanine (UMA).[HAMAP-Rule:MF_00639] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
d-Glutamic acid-adding enzyme (MurD) catalyses the essential addition of d-glutamic acid to the cytoplasmic peptidoglycan precursor UDP-N-acetylmuramoyl-l-alanine, and as such it represents an important antibacterial drug-discovery target enzyme. Based on a series of naphthalene-N-sulfonyl-d-Glu derivatives synthesised recently, we synthesised two series of new, optimised sulfonamide inhibitors of MurD that incorporate rigidified mimetics of d-Glu. The compounds that contained either constrained d-Glu or related rigid d-Glu mimetics showed significantly better inhibitory activities than the parent compounds, thereby confirming the advantage of molecular rigidisation in the design of MurD inhibitors. The binding modes of the best inhibitors were examined with high-resolution NMR spectroscopy and X-ray crystallography. We have solved a new crystal structure of the complex of MurD with an inhibitor bearing a 4-aminocyclohexane-1,3-dicarboxyl moiety. These data provide an additional step towards the development of sulfonamide inhibitors with potential antibacterial activities. | |||
Second-generation sulfonamide inhibitors of d-glutamic acid-adding enzyme: Activity optimisation with conformationally rigid analogues of d-glutamic acid.,Sosic I, Barreteau H, Simcic M, Sink R, Cesar J, Zega A, Grdadolnik SG, Contreras-Martel C, Dessen A, Amoroso A, Joris B, Blanot D, Gobec S Eur J Med Chem. 2011 Apr 9. PMID:21524830<ref>PMID:21524830</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2xpc" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Mur ligase|Mur ligase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | |||
[[ | |||
== | |||
< | |||
[[Category: Escherichia coli]] | [[Category: Escherichia coli]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Amoroso | [[Category: Amoroso A]] | ||
[[Category: Barreteau | [[Category: Barreteau H]] | ||
[[Category: Blanot | [[Category: Blanot D]] | ||
[[Category: Cesar | [[Category: Cesar J]] | ||
[[Category: Contreras-Martel | [[Category: Contreras-Martel C]] | ||
[[Category: Dessen | [[Category: Dessen A]] | ||
[[Category: Gobec | [[Category: Gobec S]] | ||
[[Category: Golic-Grdadolnik | [[Category: Golic-Grdadolnik S]] | ||
[[Category: Joris | [[Category: Joris B]] | ||
[[Category: Simcic | [[Category: Simcic M]] | ||
[[Category: Sink | [[Category: Sink R]] | ||
[[Category: Sosic | [[Category: Sosic I]] | ||
Latest revision as of 11:02, 23 August 2023
Second-generation sulfonamide inhibitors of MurD: Activity optimisation with conformationally rigid analogues of D-glutamic acidSecond-generation sulfonamide inhibitors of MurD: Activity optimisation with conformationally rigid analogues of D-glutamic acid
Structural highlights
FunctionMURD_ECOLI Cell wall formation. Catalyzes the addition of glutamate to the nucleotide precursor UDP-N-acetylmuramoyl-L-alanine (UMA).[HAMAP-Rule:MF_00639] Publication Abstract from PubMedd-Glutamic acid-adding enzyme (MurD) catalyses the essential addition of d-glutamic acid to the cytoplasmic peptidoglycan precursor UDP-N-acetylmuramoyl-l-alanine, and as such it represents an important antibacterial drug-discovery target enzyme. Based on a series of naphthalene-N-sulfonyl-d-Glu derivatives synthesised recently, we synthesised two series of new, optimised sulfonamide inhibitors of MurD that incorporate rigidified mimetics of d-Glu. The compounds that contained either constrained d-Glu or related rigid d-Glu mimetics showed significantly better inhibitory activities than the parent compounds, thereby confirming the advantage of molecular rigidisation in the design of MurD inhibitors. The binding modes of the best inhibitors were examined with high-resolution NMR spectroscopy and X-ray crystallography. We have solved a new crystal structure of the complex of MurD with an inhibitor bearing a 4-aminocyclohexane-1,3-dicarboxyl moiety. These data provide an additional step towards the development of sulfonamide inhibitors with potential antibacterial activities. Second-generation sulfonamide inhibitors of d-glutamic acid-adding enzyme: Activity optimisation with conformationally rigid analogues of d-glutamic acid.,Sosic I, Barreteau H, Simcic M, Sink R, Cesar J, Zega A, Grdadolnik SG, Contreras-Martel C, Dessen A, Amoroso A, Joris B, Blanot D, Gobec S Eur J Med Chem. 2011 Apr 9. PMID:21524830[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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