View source for 6lk2


==Crystal structure of Providencia alcalifaciens 3-dehydroquinate synthase (DHQS) in complex with Mg2+, NAD and chlorogenic acid==
<StructureSection load='6lk2' size='340' side='right'caption='[[6lk2]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6lk2]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Providencia_alcalifaciens_f90-2004 Providencia alcalifaciens f90-2004]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6LK2 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6LK2 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7LH:(1R,3R,4S,5R)-3-[3-[3,4-bis(oxidanyl)phenyl]propanoyloxy]-1,4,5-tris(oxidanyl)cyclohexane-1-carboxylic+acid'>7LH</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">aroB, HMPREF1562_0140 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1256987 Providencia alcalifaciens F90-2004])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/3-dehydroquinate_synthase 3-dehydroquinate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.3.4 4.2.3.4] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6lk2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6lk2 OCA], [http://pdbe.org/6lk2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6lk2 RCSB], [http://www.ebi.ac.uk/pdbsum/6lk2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6lk2 ProSAT]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/X6Q997_9GAMM X6Q997_9GAMM]] Catalyzes the conversion of 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) to dehydroquinate (DHQ).[HAMAP-Rule:MF_00110] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Chlorogenic acid (CGA) is a phenolic compound with well-known antibacterial properties against pathogens. In this study, structural and biochemical characterization display the inhibitory role of CGA against the enzyme of the shikimate pathway, a well characterized drug target in several pathogens. Here, we report the crystal structures of dehydroquinate synthase (DHQS), the second enzyme of the shikimate pathway, from Providencia alcalifaciens (PaDHQS), in binary complex with NAD and ternary complex with NAD and CGA. Structural analyses reveal that CGA occupies the substrate position in the active site of PaDHQS, which disables domain movements, leaving the enzyme in open and catalysis incompetent state. The binding analyses by ITC and SPR show that CGA binds to PaDHQS with a K D value of 6.3 muM and 0.5 muM respectively. In vitro enzyme inhibition studies show that CGA inhibits PaDHQS with a K i of 235 +/- 21 muM; while it inhibits the growth of Providencia alcalifaciens, Moraxella catarrhalis, Staphylococcus aureus and Escherichia coli with MIC values of 60 to 100 muM. In the presence of aromatic amino acids supplied externally, CGA doesn't show the toxic effect. These results, along with the observations of the inhibition of DAHP regulatory domain by CGA in our previous study, suggest that CGA binds to shikimate pathway enzymes with high affinity and inhibits their catalysis, and can be further exploited for designing novel drug-like molecules.Importance The shikimate pathway is an attractive target for the development of herbicides and antimicrobial agents as it is essential in plants, bacteria and apicomplexan parasites, but absent in humans. The enzymes of shikimate pathway are conserved among bacteria. Thus, the inhibitors of the shikimate pathway will act on wide range of pathogens. We have identified that chlorogenic acid targets the enzymes of shikimate pathway. The crystal structure of dehydroquinate synthase the second enzyme of the pathway, in complex with chlorogenic acid and enzymatic inhibition studies explain the mechanism of inhibition of chlorogenic acid. These results suggest that chlorogenic acid has a good chemical scaffold and have important implications for the further development as potent inhibitor of shikimate pathway enzymes.

Structural and biochemical analysis reveal chlorogenic acid inhibits the shikimate pathway.,Neetu N, Katiki M, Dev A, Gaur S, Tomar S, Kumar P J Bacteriol. 2020 Jul 13. pii: JB.00248-20. doi: 10.1128/JB.00248-20. PMID:32661075<ref>PMID:32661075</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6lk2" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: 3-dehydroquinate synthase]]
[[Category: Large Structures]]
[[Category: Providencia alcalifaciens f90-2004]]
[[Category: Katiki, M]]
[[Category: Kumar, P]]
[[Category: Neetu, N]]
[[Category: Chlorogenic acid]]
[[Category: Cytoplasm]]
[[Category: Lyase]]
[[Category: Metal-binding]]
[[Category: Nad-binding]]
[[Category: Rossmann fold]]