6r8g

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Current revision (12:17, 24 January 2024) (edit) (undo)
 
Line 3: Line 3:
<StructureSection load='6r8g' size='340' side='right'caption='[[6r8g]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
<StructureSection load='6r8g' size='340' side='right'caption='[[6r8g]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
-
<table><tr><td colspan='2'>[[6r8g]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Plafa Plafa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6R8G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6R8G FirstGlance]. <br>
+
<table><tr><td colspan='2'>[[6r8g]] is a 4 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=6R8G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6R8G FirstGlance]. <br>
-
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=JUT:4-[3,4-bis(fluoranyl)phenyl]-1,3-thiazol-2-amine'>JUT</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene></td></tr>
+
</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&#8491;</td></tr>
-
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[5nfr|5nfr]]</div></td></tr>
+
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=JUT:4-[3,4-bis(fluoranyl)phenyl]-1,3-thiazol-2-amine'>JUT</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene></td></tr>
-
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Malate_dehydrogenase Malate dehydrogenase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.37 1.1.1.37] </span></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=6r8g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r8g OCA], [https://pdbe.org/6r8g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6r8g RCSB], [https://www.ebi.ac.uk/pdbsum/6r8g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6r8g ProSAT]</span></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=6r8g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r8g OCA], [https://pdbe.org/6r8g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6r8g RCSB], [https://www.ebi.ac.uk/pdbsum/6r8g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6r8g ProSAT]</span></td></tr>
</table>
</table>
-
<div style="background-color:#fffaf0;">
+
== Function ==
-
== Publication Abstract from PubMed ==
+
[https://www.uniprot.org/uniprot/Q6VVP7_PLAFA Q6VVP7_PLAFA]
-
Malaria remains a major threat to human health, as strains resistant to current therapeutics are discovered. Efforts in finding new drug targets are hampered by the lack of sufficiently specific tools to provide target validation prior to initiating expensive drug discovery projects. Thus, new approaches that can rapidly enable drug target validation are of significant interest. In this manuscript we present the crystal structure of malate dehydrogenase from Plasmodium falciparum (PfMDH) at 2.4 A resolution and structure-based mutagenic experiments interfering with the inter-oligomeric interactions of the enzyme. We report decreased thermal stability, significantly decreased specific activity and kinetic parameters of PfMDH mutants upon mutagenic disruption of either oligomeric interface. In contrast, stabilization of one of the interfaces resulted in increased thermal stability, increased substrate/cofactor affinity and hyperactivity of the enzyme towards malate production at sub-millimolar substrate concentrations. Furthermore, the presented data show that our designed PfMDH mutant could be used as specific inhibitor of the wild type PfMDH activity, as mutated PfMDH copies were shown to be able to self-incorporate into the native assembly upon introduction in vitro, yielding deactivated mutant:wild-type species. These data provide an insight into the role of oligomeric assembly in regulation of PfMDH activity and reveal that recombinant mutants could be used as probe tool for specific modification of the wild type PfMDH activity, thus offering the potential to validate its druggability in vivo without recourse to complex genetics or initial tool compounds. Such tool compounds often lack specificity between host or pathogen proteins (or are toxic in in vivo trials) and result in difficulties in assessing cause and effect-particularly in cases when the enzymes of interest possess close homologs within the human host. Furthermore, our oligomeric interference approach could be used in the future in order to assess druggability of other challenging human pathogen drug targets.
+
-
 
+
-
Oligomeric interfaces as a tool in drug discovery: Specific interference with activity of malate dehydrogenase of Plasmodium falciparum in vitro.,Lunev S, Butzloff S, Romero AR, Linzke M, Batista FA, Meissner KA, Muller IB, Adawy A, Wrenger C, Groves MR PLoS One. 2018 Apr 25;13(4):e0195011. doi: 10.1371/journal.pone.0195011., eCollection 2018. PMID:29694407<ref>PMID:29694407</ref>
+
-
 
+
-
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+
-
</div>
+
-
<div class="pdbe-citations 6r8g" style="background-color:#fffaf0;"></div>
+
==See Also==
==See Also==
*[[Malate Dehydrogenase 3D structures|Malate Dehydrogenase 3D structures]]
*[[Malate Dehydrogenase 3D structures|Malate Dehydrogenase 3D structures]]
-
== References ==
 
-
<references/>
 
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
-
[[Category: Malate dehydrogenase]]
+
[[Category: Plasmodium falciparum]]
-
[[Category: Plafa]]
+
[[Category: Calderone V]]
-
[[Category: Calderone, V]]
+
[[Category: Domling A]]
-
[[Category: Domling, A]]
+
[[Category: Gentili M]]
-
[[Category: Gentili, M]]
+
[[Category: Groves M]]
-
[[Category: Groves, M]]
+
[[Category: Lunev S]]
-
[[Category: Lunev, S]]
+
[[Category: Popowicz G]]
-
[[Category: Popowicz, G]]
+
[[Category: Romero AR]]
-
[[Category: Romero, A R]]
+
[[Category: Sattler M]]
-
[[Category: Sattler, M]]
+
-
[[Category: Oxidoreductase]]
+

Current revision

Crystal structure of malate dehydrogenase from Plasmodium Falciparum in complex with 4-(3,4-difluorophenyl)thiazol-2-amine

PDB ID 6r8g

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6r8g"
Personal tools