1u5c: Difference between revisions

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-[[Image:1u5c.gif|left|200px]]<br /><applet load="1u5c" size="450" color="white" frame="true" align="right" spinBox="true"
-caption="1u5c, resolution 2.65&Aring;" />
-'''Plasmodium falciparum lactate dehydrogenase complexed with 3,7-dihydroxynaphthalene-2-carboxylic acid and NAD+'''<br />
-==Overview==
+==Plasmodium falciparum lactate dehydrogenase complexed with 3,7-dihydroxynaphthalene-2-carboxylic acid and NAD+==
-Gossypol is a di-sesquiterpene natural-product in the form of a, functionalised binaphthyl and is isolated from cotton plants. The compound, has long been known to exhibit anti-malarial and other biological, activities. Previous studies have indicated that compounds of this type, target Plasmodium falciparum lactate dehydrogenase (pfLDH), an essential, enzyme for energy generation within the parasite. In this study, we report, that simple naphthalene-based compounds, the core of the gossypol, structure, exhibit weak inhibition of the parasite lactate dehydrogenase., Crystal structures of the complexes formed by binding of these, naphthalene-based compounds to their target enzyme have been used to, delineate the molecular features likely to form the gossypol binding site., Two modes of binding are observed: one overlapping the pyruvate but not, the co-factor site, the other bridging the binding sites for the co-factor, nicontinamide group and pyruvate substrate. This latter site encompasses, molecular features unique to Plasmodium forms of LDH and is likely to, represent the mode of binding for gossypol derivatives that show, selectivity for the parasite enzymes. We also report a substrate analogue, that unexpectedly binds within the adenine pocket of the co-factor groove., Although these core pharmacophore-like molecules only exhibit low levels, of inhibitory activity, these molecular snapshots provide a rational basis, for renewed structure-based development of naphthalene-based compounds as, anti-malarial agents.
+<StructureSection load='1u5c' size='340' side='right'caption='[[1u5c]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1u5c]] is a 1 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=1U5C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1U5C 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]] 2.65&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BIK:3,7-DIHYDROXY-2-NAPHTHOIC+ACID'>BIK</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</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=1u5c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1u5c OCA], [https://pdbe.org/1u5c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1u5c RCSB], [https://www.ebi.ac.uk/pdbsum/1u5c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1u5c ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/LDH_PLAFD LDH_PLAFD]
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/u5/1u5c_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1u5c ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Gossypol is a di-sesquiterpene natural-product in the form of a functionalised binaphthyl and is isolated from cotton plants. The compound has long been known to exhibit anti-malarial and other biological activities. Previous studies have indicated that compounds of this type target Plasmodium falciparum lactate dehydrogenase (pfLDH), an essential enzyme for energy generation within the parasite. In this study, we report that simple naphthalene-based compounds, the core of the gossypol structure, exhibit weak inhibition of the parasite lactate dehydrogenase. Crystal structures of the complexes formed by binding of these naphthalene-based compounds to their target enzyme have been used to delineate the molecular features likely to form the gossypol binding site. Two modes of binding are observed: one overlapping the pyruvate but not the co-factor site, the other bridging the binding sites for the co-factor nicontinamide group and pyruvate substrate. This latter site encompasses molecular features unique to Plasmodium forms of LDH and is likely to represent the mode of binding for gossypol derivatives that show selectivity for the parasite enzymes. We also report a substrate analogue that unexpectedly binds within the adenine pocket of the co-factor groove. Although these core pharmacophore-like molecules only exhibit low levels of inhibitory activity, these molecular snapshots provide a rational basis for renewed structure-based development of naphthalene-based compounds as anti-malarial agents.
-==About this Structure==
+Mapping the binding site for gossypol-like inhibitors of Plasmodium falciparum lactate dehydrogenase.,Conners R, Schambach F, Read J, Cameron A, Sessions RB, Vivas L, Easton A, Croft SL, Brady RL Mol Biochem Parasitol. 2005 Aug;142(2):137-48. Epub 2005 Apr 18. PMID:15978953<ref>PMID:15978953</ref>
-U5C is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum] with NAD and BIK as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/L-lactate_dehydrogenase L-lactate dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.27 1.1.1.27] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1U5C OCA].
-==Reference==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-Mapping the binding site for gossypol-like inhibitors of Plasmodium falciparum lactate dehydrogenase., Conners R, Schambach F, Read J, Cameron A, Sessions RB, Vivas L, Easton A, Croft SL, Brady RL, Mol Biochem Parasitol. 2005 Aug;142(2):137-48. Epub 2005 Apr 18. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15978953 15978953]
+</div>
-[[Category: L-lactate dehydrogenase]]
+<div class="pdbe-citations 1u5c" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Lactate dehydrogenase 3D structures|Lactate dehydrogenase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
 [[Category: Plasmodium falciparum]]
-[[Category: Single protein]]
+[[Category: Brady RL]]
-[[Category: Brady, R.L.]]
+[[Category: Cameron A]]
-[[Category: Cameron, A.]]
+[[Category: Conners R]]
-[[Category: Conners, R.]]
+[[Category: Read J]]
-[[Category: Read, J.]]
+[[Category: Schambach F]]
-[[Category: Schambach, F.]]
+[[Category: Sessions RB]]
-[[Category: Sessions, R.B.]]
-[[Category: BIK]]
-[[Category: NAD]]
-[[Category: protein-ligand complex]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 03:51:09 2007''