9c4m
From Proteopedia
(Difference between revisions)
(New page: '''Unreleased structure''' The entry 9c4m is ON HOLD Authors: Harris, S.F., Wu, P. Description: Crystal Structure of A. baumannii GuaB dCBS with inhibitor G6 (3826) [[Category: Unrelea...) |
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal Structure of A. baumannii GuaB dCBS with inhibitor G6 (3826)== | |
| + | <StructureSection load='9c4m' size='340' side='right'caption='[[9c4m]], [[Resolution|resolution]] 2.48Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9c4m]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Acinetobacter_baumannii Acinetobacter baumannii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9C4M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9C4M FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.48Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1AUF:(2~{S})-~{N}-(4-chloranyl-3-morpholin-4-yl-phenyl)-2-[[3-(hydroxymethyl)quinolin-6-yl]amino]propanamide'>A1AUF</scene>, <scene name='pdbligand=IMP:INOSINIC+ACID'>IMP</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=9c4m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9c4m OCA], [https://pdbe.org/9c4m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9c4m RCSB], [https://www.ebi.ac.uk/pdbsum/9c4m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9c4m ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/IMDH_ACICA IMDH_ACICA] Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Inosine 5'-monophosphate dehydrogenase (IMPDH), known as GuaB in bacteria, catalyzes the rate-limiting step in de novo guanine biosynthesis and is conserved from humans to bacteria. We developed a series of potent inhibitors that selectively target GuaB over its human homolog. Here, we show that these GuaB inhibitors are bactericidal, generate phenotypic signatures that are distinct from other antibiotics, and elicit different time-kill kinetics and regulatory responses in two important Gram-negative pathogens: Acinetobacter baumannii and Escherichia coli. Specifically, the GuaB inhibitor G6 rapidly kills A. baumannii but only kills E. coli after 24 h. After exposure to G6, the expression of genes involved in purine biosynthesis and stress responses change in opposite directions while siderophore biosynthesis is downregulated in both species. Our results suggest that different species respond to GuaB inhibition using distinct regulatory programs and possibly explain the different bactericidal kinetics upon GuaB inhibition. The comparison highlights opportunities for developing GuaB inhibitors as novel antibiotics.IMPORTANCEA. baumannii is a priority bacterial pathogen for which development of new antibiotics is urgently needed due to the emergence of multidrug resistance. We recently developed a series of specific inhibitors against GuaB, a bacterial inosine 5'-monophosphate dehydrogenase, and achieved sub-micromolar minimum inhibitory concentrations against A. baumannii. GuaB catalyzes the rate-limiting step of de novo guanine biosynthesis and is highly conserved across bacterial pathogens. This study shows that inhibition of GuaB induced a bacterial morphological profile distinct from that of other classes of antibiotics, highlighting a novel mechanism of action. Moreover, our transcriptomic analysis showed that regulation of de novo purine biosynthesis and stress responses of A. baumannii upon GuaB inhibition differed significantly from that of E. coli. | ||
| - | + | Differential effects of inosine monophosphate dehydrogenase (IMPDH/GuaB) inhibition in Acinetobacter baumannii and Escherichia coli.,Peng Y, Moffat JG, DuPai C, Kofoed EM, Skippington E, Modrusan Z, Gloor SL, Clark K, Xu Y, Li S, Chen L, Liu X, Wu P, Harris SF, Wang S, Crawford TD, Li CS, Liu Z, Wai J, Tan M-W J Bacteriol. 2024 Sep 5:e0010224. doi: 10.1128/jb.00102-24. PMID:39235234<ref>PMID:39235234</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 9c4m" style="background-color:#fffaf0;"></div> |
| - | [[Category: | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Acinetobacter baumannii]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Harris SF]] | ||
| + | [[Category: Wu P]] | ||
Current revision
Crystal Structure of A. baumannii GuaB dCBS with inhibitor G6 (3826)
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