View source for 9auz


==Crystal structure of S. aureus GuaB dCBS with inhibitor GNE9979==
<StructureSection load='9auz' size='340' side='right'caption='[[9auz]], [[Resolution|resolution]] 1.94&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9auz]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9AUZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9AUZ 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]] 1.94&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IMP:INOSINIC+ACID'>IMP</scene>, <scene name='pdbligand=VP4:(2~{S})-~{N}-[4-chloranyl-3-(dimethylamino)phenyl]-2-[[3-(hydroxymethyl)quinolin-6-yl]amino]propanamide'>VP4</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=9auz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9auz OCA], [https://pdbe.org/9auz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9auz RCSB], [https://www.ebi.ac.uk/pdbsum/9auz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9auz ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/IMDH_STAA3 IMDH_STAA3] 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.[HAMAP-Rule:MF_01964]
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Guanine nucleotides are required for growth and viability of cells due to their structural role in DNA and RNA, and their regulatory roles in translation, signal transduction, and cell division. The natural antibiotic mycophenolic acid (MPA) targets the rate-limiting step in de novo guanine nucleotide biosynthesis executed by inosine-5 -monophosphate dehydrogenase (IMPDH). MPA is used clinically as an immunosuppressant, but whether in vivo inhibition of bacterial IMPDH (GuaB) is a valid antibacterial strategy is controversial. Here, we describe the discovery of extremely potent small molecule GuaB inhibitors (GuaBi) specific to pathogenic bacteria with a low frequency of on-target spontaneous resistance and bactericidal efficacy in vivo against Acinetobacter baumannii mouse models of infection. The spectrum of GuaBi activity includes multidrug-resistant pathogens that are a critical priority of new antibiotic development. Co-crystal structures of A. baumannii, Staphylococcus aureus, and Escherichia coli GuaB proteins bound to inhibitors show comparable binding modes of GuaBi across species and identifies key binding site residues that are predictive of whole-cell activity across both Gram-positive and Gram-negative clades of Bacteria. The clear in vivo efficacy of these small molecule GuaB inhibitors in a model of A. baumannii infection validates GuaB as an essential antibiotic target. IMPORTANCE: The emergence of multidrug-resistant bacteria worldwide has renewed interest in discovering antibiotics with novel mechanism of action. For the first time ever, we demonstrate that pharmacological inhibition of de novo guanine biosynthesis is bactericidal in a mouse model of Acinetobacter baumannii infection. Structural analyses of novel inhibitors explain differences in biochemical and whole-cell activity across bacterial clades and underscore why this discovery may have broad translational impact on treatment of the most recalcitrant bacterial infections.

Discovery of GuaB inhibitors with efficacy against Acinetobacter baumannii infection.,Kofoed EM, Aliagas I, Crawford T, Mao J, Harris SF, Xu M, Wang S, Wu P, Ma F, Clark K, Sims J, Xu Y, Peng Y, Skippington E, Yang Y, Reeder J, Ubhayakar S, Baumgardner M, Yan Z, Chen J, Park S, Zhang H, Yen C-W, Lorenzo M, Skelton N, Liang X, Chen L, Hoag B, Li CS, Liu Z, Wai J, Liu X, Liang J, Tan MW mBio. 2024 Oct 16;15(10):e0089724. doi: 10.1128/mbio.00897-24. Epub 2024 Aug 29. PMID:39207111<ref>PMID:39207111</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9auz" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Staphylococcus aureus]]
[[Category: Harris SF]]
[[Category: Wu P]]