View source for 6jwv


==Crystal structure of Plasmodium falciparum HPPK-DHPS A437G with STZ-DHP==
<StructureSection load='6jwv' size='340' side='right'caption='[[6jwv]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6jwv]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6JWV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6JWV 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]] 2.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PH2:2-AMINO-6-HYDROXYMETHYL-7,8-DIHYDRO-3H-PTERIDIN-4-ONE'>PH2</scene>, <scene name='pdbligand=XTZ:4-{[(2-AMINO-4-OXO-3,4,7,8-TETRAHYDROPTERIDIN-6-YL)METHYL]AMINO}-N-(1,3-THIAZOL-2-YL)BENZENESULFONAMIDE'>XTZ</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=6jwv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jwv OCA], [https://pdbe.org/6jwv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6jwv RCSB], [https://www.ebi.ac.uk/pdbsum/6jwv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6jwv ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q25704_PLAFA Q25704_PLAFA] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The clinical efficacy of sulfa drugs as antimalarials has declined owing to the evolution of resistance in Plasmodium falciparum (Pf) malaria parasites. In order to understand the basis of this resistance and to design more effective antimalarials, we have solved 13 structures of the bifunctional enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK)-dihydropteroate synthase (DHPS) from wild-type (WT) P. falciparum and sulfa-resistant mutants, both as apoenzyme and as complexes with pteroate (PTA) and sulfa derivatives. The structures of these complexes show that PTA, which effectively inhibits both the WT and mutants, stays in active sites without steric constraint. In contrast, parts of the sulfa compounds situated outside of the substrate envelope are in the vicinity of the resistance mutations. Steric conflict between compound and mutant residue along with increased flexibility of loop D2 in the mutants can account for the reduced compound binding affinity to the mutants. Kinetic data show that the mutants have enhanced enzyme activity compared with the WT. These PfDHPS structural insights are critical for the design of novel, substrate envelope-compliant DHPS inhibitors that are less vulnerable to resistance mutations. DATABASES: The data reported in this paper have been deposited in the Protein Data Bank, www.wwpdb.org. PDB ID codes: 6JWQ for apoWT; 6JWR, 6JWS, and 6JWT for PTA complexes of WT, A437G (3D7), and V1/S; 6JWU, 6JWV, and 6JWW for STZ-DHP complexes of WT, 3D7, and V1/S; 6JWX, 6JWY, and 6JWZ for SDX-DHP complexes of WT, 3D7, and W2; 6KCK, 6KCL, and 6KCM for Pterin/pHBA complexes of WT, TN1, and W2.

The structure of Plasmodium falciparum hydroxymethyldihydropterin pyrophosphokinase-dihydropteroate synthase reveals the basis of sulfa resistance.,Chitnumsub P, Jaruwat A, Talawanich Y, Noytanom K, Liwnaree B, Poen S, Yuthavong Y FEBS J. 2019 Dec 28. doi: 10.1111/febs.15196. PMID:31883412<ref>PMID:31883412</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6jwv" 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: Large Structures]]
[[Category: Plasmodium falciparum]]
[[Category: Chitnumsub P]]
[[Category: Jaruwat A]]
[[Category: Yuthavong Y]]