6ueg: Difference between revisions
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The | ==Pseudomonas aeruginosa LpxA Complex Structure with Ligand== | ||
<StructureSection load='6ueg' size='340' side='right'caption='[[6ueg]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6ueg]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UEG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6UEG FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=Q5G:3-({2-[(2R)-2-carbamoyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl]-2-oxoethyl}sulfanyl)propanoic+acid'>Q5G</scene></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Acyl-[acyl-carrier-protein]--UDP-N-acetylglucosamine_O-acyltransferase Acyl-[acyl-carrier-protein]--UDP-N-acetylglucosamine O-acyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.129 2.3.1.129] </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=6ueg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ueg OCA], [http://pdbe.org/6ueg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ueg RCSB], [http://www.ebi.ac.uk/pdbsum/6ueg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ueg ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/LPXA_PSEA7 LPXA_PSEA7]] Involved in the biosynthesis of lipid A, a phosphorylated glycolipid that anchors the lipopolysaccharide to the outer membrane of the cell. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The lipid A biosynthesis pathway is essential in Pseudomonas aeruginosa. LpxA and LpxD are the first and third enzymes in this pathway respectively, and are regarded as promising antibiotic targets. The unique structural similarities between these two enzymes make them suitable targets for dual-binding inhibitors, a characteristic that would decrease the likelihood of mutational resistance and increase cell-based activity. We report the discovery of multiple small molecule ligands that bind to P. aeruginosa LpxA and LpxD, including dual-binding ligands. Binding poses were determined for select compounds by X-ray crystallography. The new structures reveal a previously uncharacterized magnesium ion residing at the core of the LpxD trimer. In addition, ligand binding in the LpxD active site resulted in conformational changes in the distal C-terminal helix-bundle, which forms extensive contacts with acyl carrier protein (ACP) during catalysis. These ligand-dependent conformational changes suggest a potential allosteric influence of reaction intermediates on ACP binding, and vice versa. Taken together, the novel small molecule ligands and their crystal structures provide new chemical scaffolds for ligand discovery targeting lipid A biosynthesis, while revealing structural features of interest for future investigation of LpxD function. | |||
Discovery of dual-activity small-molecule ligands of Pseudomonas aeruginosa LpxA and LpxD using SPR and X-ray crystallography.,Kroeck KG, Sacco MD, Smith EW, Zhang X, Shoun D, Akhtar A, Darch SE, Cohen F, Andrews LD, Knox JE, Chen Y Sci Rep. 2019 Oct 29;9(1):15450. doi: 10.1038/s41598-019-51844-z. PMID:31664082<ref>PMID:31664082</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6ueg" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Chen, Y]] | |||
[[Category: Kroeck, K]] | |||
[[Category: Sacco, M]] | |||
[[Category: Acyl transferase]] | |||
[[Category: Ligand complex]] | |||
[[Category: Lpxa]] | |||
[[Category: Transferase]] | |||
[[Category: Trimer]] | |||
Revision as of 14:16, 13 November 2019
Pseudomonas aeruginosa LpxA Complex Structure with LigandPseudomonas aeruginosa LpxA Complex Structure with Ligand
Structural highlights
Function[LPXA_PSEA7] Involved in the biosynthesis of lipid A, a phosphorylated glycolipid that anchors the lipopolysaccharide to the outer membrane of the cell. Publication Abstract from PubMedThe lipid A biosynthesis pathway is essential in Pseudomonas aeruginosa. LpxA and LpxD are the first and third enzymes in this pathway respectively, and are regarded as promising antibiotic targets. The unique structural similarities between these two enzymes make them suitable targets for dual-binding inhibitors, a characteristic that would decrease the likelihood of mutational resistance and increase cell-based activity. We report the discovery of multiple small molecule ligands that bind to P. aeruginosa LpxA and LpxD, including dual-binding ligands. Binding poses were determined for select compounds by X-ray crystallography. The new structures reveal a previously uncharacterized magnesium ion residing at the core of the LpxD trimer. In addition, ligand binding in the LpxD active site resulted in conformational changes in the distal C-terminal helix-bundle, which forms extensive contacts with acyl carrier protein (ACP) during catalysis. These ligand-dependent conformational changes suggest a potential allosteric influence of reaction intermediates on ACP binding, and vice versa. Taken together, the novel small molecule ligands and their crystal structures provide new chemical scaffolds for ligand discovery targeting lipid A biosynthesis, while revealing structural features of interest for future investigation of LpxD function. Discovery of dual-activity small-molecule ligands of Pseudomonas aeruginosa LpxA and LpxD using SPR and X-ray crystallography.,Kroeck KG, Sacco MD, Smith EW, Zhang X, Shoun D, Akhtar A, Darch SE, Cohen F, Andrews LD, Knox JE, Chen Y Sci Rep. 2019 Oct 29;9(1):15450. doi: 10.1038/s41598-019-51844-z. PMID:31664082[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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