View source for 4pzv


==Crystal structure of Francisella tularensis HPPK-DHPS in complex with bisubstrate analog HPPK inhibitor J1D==
<StructureSection load='4pzv' size='340' side='right'caption='[[4pzv]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4pzv]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Francisella_tularensis_subsp._tularensis_SCHU_S4 Francisella tularensis subsp. tularensis SCHU S4]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PZV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PZV 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]] 1.704&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=J1D:5-{[2-({N-[(2-AMINO-7,7-DIMETHYL-4-OXO-3,4,7,8-TETRAHYDROPTERIDIN-6-YL)CARBONYL]GLYCYL}AMINO)ETHYL]SULFONYL}-5-DEOXYADENOSINE'>J1D</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=4pzv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pzv OCA], [https://pdbe.org/4pzv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4pzv RCSB], [https://www.ebi.ac.uk/pdbsum/4pzv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4pzv ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q5NGA7_FRATT Q5NGA7_FRATT] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Two valid targets for antibiotic development, 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) and dihydropteroate synthase (DHPS), catalyze consecutive reactions in folate biosynthesis. In Francisella tularensis (Ft), these two activities are contained in a single protein, FtHPPK-DHPS. While Pemble and coworkers determined the structure of FtHPPK-DHPS, they were unable to measure the kinetic parameters of the enzyme (PloS one 5, e14165). In this study, we elucidated the binding and inhibitory activities of two HPPK inhibitors (HP-18 and HP-26) against FtHPPK-DHPS, determined the structure of FtHPPK-DHPS in complex with HP-26, and measured the kinetic parameters for the dual enzymatic activities of FtHPPK-DHPS. The biochemical analyses showed that HP-18 and HP-26 have significant isozyme selectivity and that FtHPPK-DHPS is unique in that the catalytic efficiency of its DHPS activity is only 1/2.6x105 that of Escherichia coli DHPS. Sequence and structural analyses suggest that HP-26 is an excellent lead for developing tularemia therapeutics and that the very low DHPS activity is due, at least in part, to the lack of a key residue that interacts with the substrate p-aminobenzoic acid (pABA). A BLAST search of 10 F. tularensis genomes indicated that the bacterium contains a single FtHPPK-DHPS. The marginal DHPS activity and the singular existence of FtHPPK-DHPS in F. tularensis make this bacterium more vulnerable to DHPS inhibitors. Current sulfa drugs are ineffective against tularemia; new inhibitors targeting the unique pABA-binding pocket may be effective and less subject to resistance because mutation may make the marginal DHPS activity unable to support the growth of F. tularensis. This article is protected by copyright. All rights reserved.

Structural enzymology and inhibition of the bifunctional folate pathway enzyme HPPK-DHPS from the biowarfare agent Francisella tularensis.,Shaw GX, Li Y, Shi G, Wu Y, Cherry S, Needle D, Zhang D, Tropea JE, Waugh DS, Yan H, Ji X FEBS J. 2014 Jun 27. doi: 10.1111/febs.12896. PMID:24975935<ref>PMID:24975935</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4pzv" style="background-color:#fffaf0;"></div>

==See Also==
*[[Dihydropteroate synthase 3D structures|Dihydropteroate synthase 3D structures]]
*[[HPPK 3D structures|HPPK 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Francisella tularensis subsp. tularensis SCHU S4]]
[[Category: Large Structures]]
[[Category: Ji X]]
[[Category: Shaw GX]]
[[Category: Shi G]]