View source for 3qbc


==Structure and design of a new pterin site inhibitor of S. aureus HPPK==
<StructureSection load='3qbc' size='340' side='right'caption='[[3qbc]], [[Resolution|resolution]] 1.65&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3qbc]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus_subsp._aureus_Mu50 Staphylococcus aureus subsp. aureus Mu50]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QBC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QBC 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]] 1.65&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B55:2-AMINO-8-SULFANYL-1,9-DIHYDRO-6H-PURIN-6-ONE'>B55</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=3qbc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qbc OCA], [https://pdbe.org/3qbc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qbc RCSB], [https://www.ebi.ac.uk/pdbsum/3qbc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qbc ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/A0A0H3JXR3_STAAM A0A0H3JXR3_STAAM] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The first structural and biophysical data on the folate biosynthesis pathway enzyme and drug target, 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (SaHPPK), from the pathogen Staphylococcus aureus is presented. HPPK is the second essential enzyme in the pathway catalysing the pyrophosphoryl transfer from cofactor (ATP) to the substrate (6-hydroxymethyl-7,8-dihydropterin, HMDP). In-silico screening identified 8-mercaptoguanine which was shown to bind with an equilibrium dissociation constant, K(d), of approximately 13 microM as measured by isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR). An IC(50) of approximately 41 microM was determined by means of a luminescent kinase assay. In contrast to the biological substrate, the inhibitor has no requirement for magnesium or the ATP cofactor for competitive binding to the substrate site. The 1.65 A resolution crystal structure of the inhibited complex showed that it binds in the pterin site and shares many of the key intermolecular interactions of the substrate. Chemical shift and (15)N heteronuclear NMR measurements reveal that the fast motion of the pterin-binding loop (L2) is partially dampened in the SaHPPK/HMDP/alpha,beta-methylene adenosine 5'-triphosphate (AMPCPP) ternary complex, but the ATP loop (L3) remains mobile on the micros-ms timescale. In contrast, for the SaHPPK/8-mercaptoguanine/AMPCPP ternary complex, the loop L2 becomes rigid on the fast timescale and the L3 loop also becomes more ordered--an observation that correlates with the large entropic penalty associated with inhibitor binding as revealed by ITC. NMR data, including (15)N-(1)H residual dipolar coupling measurements, indicate that the sulfur atom in the inhibitor is important for stabilizing and restricting important motions of the L2 and L3 catalytic loops in the inhibited ternary complex. This work describes a comprehensive analysis of a new HPPK inhibitor, and may provide a foundation for the development of novel antimicrobials targeting the folate biosynthetic pathway.

Structure of S. aureus HPPK and the discovery of a new substrate site inhibitor.,Chhabra S, Dolezal O, Collins BM, Newman J, Simpson JS, Macreadie IG, Fernley R, Peat TS, Swarbrick JD PLoS One. 2012;7(1):e29444. Epub 2012 Jan 19. PMID:22276115<ref>PMID:22276115</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3qbc" style="background-color:#fffaf0;"></div>

==See Also==
*[[HPPK 3D structures|HPPK 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Staphylococcus aureus subsp. aureus Mu50]]
[[Category: Chhabra S]]
[[Category: Peat TS]]
[[Category: Swarbrick JD]]