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{{STRUCTURE_3zm5|  PDB=3zm5  |  SCENE=  }}
==CRYSTAL STRUCTURE OF MURF LIGASE IN COMPLEX WITH CYANOTHIOPHENE INHIBITOR==
===CRYSTAL STRUCTURE OF MURF LIGASE IN COMPLEX WITH CYANOTHIOPHENE INHIBITOR===
<StructureSection load='3zm5' size='340' side='right' caption='[[3zm5]], [[Resolution|resolution]] 2.94&Aring;' scene=''>
{{ABSTRACT_PUBMED_23786712}}
== Structural highlights ==
<table><tr><td colspan='2'>[[3zm5]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Streptococcus_pneumoniae_r6 Streptococcus pneumoniae r6]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZM5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ZM5 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=IGM:2,4-BIS(CHLORANYL)-N-[3-CYANO-6-[(4-HYDROXYPHENYL)METHYL]-5,7-DIHYDRO-4H-THIENO[2,3-C]PYRIDIN-2-YL]-5-MORPHOLIN-4-YLSULFONYL-BENZAMIDE'>IGM</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3zl8|3zl8]], [[3zm6|3zm6]]</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/UDP-N-acetylmuramoyl-tripeptide--D-alanyl-D-alanine_ligase UDP-N-acetylmuramoyl-tripeptide--D-alanyl-D-alanine ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.2.10 6.3.2.10] </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=3zm5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zm5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3zm5 RCSB], [http://www.ebi.ac.uk/pdbsum/3zm5 PDBsum]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Peptidoglycan is an essential component of the bacterial cell wall, and enzymes involved in its biosynthesis represent validated targets for antibacterial drug discovery. MurF catalyzes the final intracellular peptidoglycan biosynthesis step: the addition of d-Ala-d-Ala to the nucleotide precursor UDP-MurNAc-l-Ala-gamma-d-Glu-meso-DAP (or l-Lys). As MurF has no human counterpart, it represents an attractive target for the development of new antibacterial drugs. Using recently published cyanothiophene inhibitors of MurF from Streptococcus pneumoniae as a starting point, we designed and synthesized a series of structurally related derivatives and investigated their inhibition of MurF enzymes from different bacterial species. Systematic structural modifications of the parent compounds resulted in a series of nanomolar inhibitors of MurF from S. pneumoniae and micromolar inhibitors of MurF from Escherichia coli and Staphylococcus aureus. Some of the inhibitors also show antibacterial activity against S. pneumoniae R6. These findings, together with two new co-crystal structures, represent an excellent starting point for further optimization toward effective novel antibacterials.


==Function==
Structure-activity relationships of new cyanothiophene inhibitors of the essential peptidoglycan biosynthesis enzyme MurF.,Hrast M, Turk S, Sosic I, Knez D, Randall CP, Barreteau H, Contreras-Martel C, Dessen A, O'Neill AJ, Mengin-Lecreulx D, Blanot D, Gobec S Eur J Med Chem. 2013 May 21;66C:32-45. doi: 10.1016/j.ejmech.2013.05.013. PMID:23786712<ref>PMID:23786712</ref>
[[http://www.uniprot.org/uniprot/Q8DNV6_STRR6 Q8DNV6_STRR6]] Involved in cell wall formation. Catalyzes the final step in the synthesis of UDP-N-acetylmuramoyl-pentapeptide, the precursor of murein (By similarity).[RuleBase:RU004136]


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[3zm5]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Streptococcus_pneumoniae_r6 Streptococcus pneumoniae r6]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZM5 OCA].
</div>
 
== References ==
==Reference==
<references/>
<ref group="xtra">PMID:023786712</ref><references group="xtra"/><references/>
__TOC__
</StructureSection>
[[Category: Streptococcus pneumoniae r6]]
[[Category: Streptococcus pneumoniae r6]]
[[Category: UDP-N-acetylmuramoyl-tripeptide--D-alanyl-D-alanine ligase]]
[[Category: UDP-N-acetylmuramoyl-tripeptide--D-alanyl-D-alanine ligase]]
[[Category: Barreteau, H.]]
[[Category: Barreteau, H]]
[[Category: Blanot, D.]]
[[Category: Blanot, D]]
[[Category: Contreras-Martel, C.]]
[[Category: Contreras-Martel, C]]
[[Category: Dessen, A.]]
[[Category: Dessen, A]]
[[Category: Gobec, S.]]
[[Category: Gobec, S]]
[[Category: Hrast, M.]]
[[Category: Hrast, M]]
[[Category: Knez, D.]]
[[Category: Knez, D]]
[[Category: Mengin-Lecreulx, D.]]
[[Category: Mengin-Lecreulx, D]]
[[Category: ONeill, A J.]]
[[Category: ONeill, A J]]
[[Category: Randall, C P.]]
[[Category: Randall, C P]]
[[Category: Sosic, I.]]
[[Category: Sosic, I]]
[[Category: Turk, S.]]
[[Category: Turk, S]]
[[Category: Adp-forming enzyme]]
[[Category: Adp-forming enzyme]]
[[Category: Atp-binding]]
[[Category: Atp-binding]]

Revision as of 12:04, 21 December 2014

CRYSTAL STRUCTURE OF MURF LIGASE IN COMPLEX WITH CYANOTHIOPHENE INHIBITORCRYSTAL STRUCTURE OF MURF LIGASE IN COMPLEX WITH CYANOTHIOPHENE INHIBITOR

Structural highlights

3zm5 is a 1 chain structure with sequence from Streptococcus pneumoniae r6. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Activity:UDP-N-acetylmuramoyl-tripeptide--D-alanyl-D-alanine ligase, with EC number 6.3.2.10
Resources:FirstGlance, OCA, RCSB, PDBsum

Publication Abstract from PubMed

Peptidoglycan is an essential component of the bacterial cell wall, and enzymes involved in its biosynthesis represent validated targets for antibacterial drug discovery. MurF catalyzes the final intracellular peptidoglycan biosynthesis step: the addition of d-Ala-d-Ala to the nucleotide precursor UDP-MurNAc-l-Ala-gamma-d-Glu-meso-DAP (or l-Lys). As MurF has no human counterpart, it represents an attractive target for the development of new antibacterial drugs. Using recently published cyanothiophene inhibitors of MurF from Streptococcus pneumoniae as a starting point, we designed and synthesized a series of structurally related derivatives and investigated their inhibition of MurF enzymes from different bacterial species. Systematic structural modifications of the parent compounds resulted in a series of nanomolar inhibitors of MurF from S. pneumoniae and micromolar inhibitors of MurF from Escherichia coli and Staphylococcus aureus. Some of the inhibitors also show antibacterial activity against S. pneumoniae R6. These findings, together with two new co-crystal structures, represent an excellent starting point for further optimization toward effective novel antibacterials.

Structure-activity relationships of new cyanothiophene inhibitors of the essential peptidoglycan biosynthesis enzyme MurF.,Hrast M, Turk S, Sosic I, Knez D, Randall CP, Barreteau H, Contreras-Martel C, Dessen A, O'Neill AJ, Mengin-Lecreulx D, Blanot D, Gobec S Eur J Med Chem. 2013 May 21;66C:32-45. doi: 10.1016/j.ejmech.2013.05.013. PMID:23786712[1]

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

References

  1. ↑ Hrast M, Turk S, Sosic I, Knez D, Randall CP, Barreteau H, Contreras-Martel C, Dessen A, O'Neill AJ, Mengin-Lecreulx D, Blanot D, Gobec S. Structure-activity relationships of new cyanothiophene inhibitors of the essential peptidoglycan biosynthesis enzyme MurF. Eur J Med Chem. 2013 May 21;66C:32-45. doi: 10.1016/j.ejmech.2013.05.013. PMID:23786712 doi:10.1016/j.ejmech.2013.05.013

3zm5, resolution 2.94Å

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