4d9p: Difference between revisions
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==Crystal structure of B. anthracis DHPS with compound 17== | ==Crystal structure of B. anthracis DHPS with compound 17== | ||
<StructureSection load='4d9p' size='340' side='right' caption='[[4d9p]], [[Resolution|resolution]] 2.26Å' scene=''> | <StructureSection load='4d9p' size='340' side='right'caption='[[4d9p]], [[Resolution|resolution]] 2.26Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4d9p]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4d9p]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bacillus_anthracis_str._A2012 Bacillus anthracis str. A2012]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4D9P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4D9P FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=Z17:(3R)-3-(7-AMINO-1-METHYL-4,5-DIOXO-1,4,5,6-TETRAHYDROPYRIMIDO[4,5-C]PYRIDAZIN-3-YL)BUTANOIC+ACID'>Z17</scene | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=Z17:(3R)-3-(7-AMINO-1-METHYL-4,5-DIOXO-1,4,5,6-TETRAHYDROPYRIMIDO[4,5-C]PYRIDAZIN-3-YL)BUTANOIC+ACID'>Z17</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=4d9p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d9p OCA], [https://pdbe.org/4d9p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4d9p RCSB], [https://www.ebi.ac.uk/pdbsum/4d9p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4d9p ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[[ | [[https://www.uniprot.org/uniprot/Q81VW8_BACAN Q81VW8_BACAN]] | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</div> | </div> | ||
<div class="pdbe-citations 4d9p" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 4d9p" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Dihydropteroate synthase 3D structures|Dihydropteroate synthase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Bacillus anthracis | [[Category: Bacillus anthracis str. A2012]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Hammoudeh | [[Category: Hammoudeh D]] | ||
[[Category: Lee | [[Category: Lee RE]] | ||
[[Category: White | [[Category: White SW]] | ||
Revision as of 11:07, 21 September 2022
Crystal structure of B. anthracis DHPS with compound 17Crystal structure of B. anthracis DHPS with compound 17
Structural highlights
FunctionPublication Abstract from PubMedDihydropteroate synthase (DHPS) is the validated drug target for sulfonamide antimicrobial therapy. However, due to widespread drug resistance and poor tolerance, the use of sulfonamide antibiotics is now limited. The pterin binding pocket in DHPS is highly conserved and is distinct from the sulfonamide binding site. It therefore represents an attractive alternative target for the design of novel antibacterial agents. We previously carried out the structural characterization of a known pyridazine inhibitor in the Bacillus anthracis DHPS pterin site and identified a number of unfavorable interactions that appear to compromise binding. With this structural information, a series of 4,5-dioxo-1,4,5,6-tetrahydropyrimido[4,5-c]pyridazines were designed to improve binding affinity. Most importantly, the N-methyl ring substitution was removed to improve binding within the pterin pocket, and the length of the side chain carboxylic acid was optimized to fully engage the pyrophosphate binding site. These inhibitors were synthesized and evaluated by an enzyme activity assay, X-ray crystallography, isothermal calorimetry, and surface plasmon resonance to obtain a comprehensive understanding of the binding interactions from structural, kinetic, and thermodynamic perspectives. This study clearly demonstrates that compounds lacking the N-methyl substitution exhibit increased inhibition of DHPS, but the beneficial effects of optimizing the side chain length are less apparent. Structure-Based Design of Novel Pyrimido[4,5-c]pyridazine Derivatives as Dihydropteroate Synthase Inhibitors with Increased Affinity.,Zhao Y, Hammoudeh D, Yun MK, Qi J, White SW, Lee RE ChemMedChem. 2012 Mar 13. doi: 10.1002/cmdc.201200049. PMID:22416048[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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