4d8a: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4d8a]] 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=4D8A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4D8A FirstGlance]. <br>
<table><tr><td colspan='2'>[[4d8a]] 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=4D8A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4D8A FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0HY:METHYL+(3R)-3-(7-AMINO-4,5-DIOXO-1,4,5,6-TETRAHYDROPYRIMIDO[4,5-C]PYRIDAZIN-3-YL)BUTANOATE'>0HY</scene>, <scene name='pdbligand=LYS:LYSINE'>LYS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.183&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0HY:METHYL+(3R)-3-(7-AMINO-4,5-DIOXO-1,4,5,6-TETRAHYDROPYRIMIDO[4,5-C]PYRIDAZIN-3-YL)BUTANOATE'>0HY</scene>, <scene name='pdbligand=LYS:LYSINE'>LYS</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=4d8a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d8a OCA], [https://pdbe.org/4d8a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4d8a RCSB], [https://www.ebi.ac.uk/pdbsum/4d8a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4d8a ProSAT]</span></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=4d8a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d8a OCA], [https://pdbe.org/4d8a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4d8a RCSB], [https://www.ebi.ac.uk/pdbsum/4d8a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4d8a ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[https://www.uniprot.org/uniprot/Q81VW8_BACAN Q81VW8_BACAN]]
[https://www.uniprot.org/uniprot/Q81VW8_BACAN Q81VW8_BACAN]  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Dihydropteroate 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<ref>PMID:22416048</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4d8a" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Dihydropteroate synthase 3D structures|Dihydropteroate synthase 3D structures]]
*[[Dihydropteroate synthase 3D structures|Dihydropteroate synthase 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>

Latest revision as of 17:28, 14 March 2024

Crystal structure of B. anthracis DHPS with compound 21Crystal structure of B. anthracis DHPS with compound 21

Structural highlights

4d8a is a 2 chain structure with sequence from Bacillus anthracis str. A2012. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.183Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

Q81VW8_BACAN

See Also

4d8a, resolution 2.18Å

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