5nfr - Revision history

OCA at 12:54, 15 November 2023

2023-11-15T12:54:34Z

←Older revision		Revision as of 12:54, 15 November 2023
Line 1:		Line 1:

	==Crystal structure of malate dehydrogenase from Plasmodium falciparum (PfMDH)==		==Crystal structure of malate dehydrogenase from Plasmodium falciparum (PfMDH)==
-	<StructureSection load='5nfr' size='340' side='right' caption='[[5nfr]], [[Resolution\|resolution]] 2.40Å' scene=''>	+	<StructureSection load='5nfr' size='340' side='right'caption='[[5nfr]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5nfr]] is a 16 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Plaf7 Plaf7~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NFR OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5NFR FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5nfr]] is a 16 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NFR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5NFR FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat"~~><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</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]] 2.4Å</td></tr>
-	~~<tr~~ id~~='gene'><td class~~="~~sblockLbl~~">~~<b>~~[[~~Gene~~\|~~Gene:~~]]~~</b></td><td class="sblockDat">PF3D7_0618500 ([http://www~~.~~ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info~~&~~srchmode=5&id=36329 PLAF7])~~</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene></td></tr>
-	<tr id='~~activity~~'><td class="sblockLbl"><b>~~Activity~~:</b></td><td class="sblockDat"><~~span class~~='~~plainlinks~~'>~~[http://en.wikipedia.org/wiki/Malate_dehydrogenase Malate dehydrogenase], with EC number [http://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=5nfr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nfr OCA], [https://pdbe.org/5nfr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5nfr RCSB], [https://www.ebi.ac.uk/pdbsum/5nfr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5nfr ProSAT]</span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5nfr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nfr OCA], [~~http~~://pdbe.org/5nfr PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5nfr RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5nfr PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5nfr ProSAT]</span></td></tr>	+
	</table>		</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/C6KT25_PLAF7 C6KT25_PLAF7]
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 20:		Line 21:

	==See Also==		==See Also==
-	*[[Malate ~~dehydrogenase~~\|Malate ~~dehydrogenase~~]]	+	*[[Malate Dehydrogenase 3D structures\|Malate Dehydrogenase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Malate dehydrogenase~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Plaf7~~]]	+	[[Category: Plasmodium falciparum 3D7]]
-	[[Category: Batista~~, F A~~]]	+	[[Category: Batista FA]]
-	[[Category: Groves~~, M R~~]]	+	[[Category: Groves MR]]
-	[[Category: Lunev, S]]	+	[[Category: Lunev S]]
-	[[Category: Romero~~, A R~~]]	+	[[Category: Romero AR]]
-	[[Category: Wrenger, C]]	+	[[Category: Wrenger C]]
-	~~[[Category: Dehydrogenase]]~~	+
-	~~[[Category: Malate metabolism]]~~	+
-	~~[[Category: Oligomerisation]]~~	+
-	~~[[Category: Oxidoreductase]]~~	+
-	~~[[Category: Plasmodium falciparum~~]]	+

OCA at 22:03, 9 August 2018

2018-08-09T22:03:01Z

←Older revision		Revision as of 22:03, 9 August 2018
Line 3:		Line 3:
	<StructureSection load='5nfr' size='340' side='right' caption='[[5nfr]], [[Resolution\|resolution]] 2.40Å' scene=''>		<StructureSection load='5nfr' size='340' side='right' caption='[[5nfr]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5nfr]] is a 16 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NFR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NFR FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5nfr]] is a 16 chain structure with sequence from [http://en.wikipedia.org/wiki/Plaf7 Plaf7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NFR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NFR FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PF3D7_0618500 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=36329 PLAF7])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Malate_dehydrogenase Malate dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.37 1.1.1.37] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Malate_dehydrogenase Malate dehydrogenase], with EC number [http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5nfr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nfr OCA], [http://pdbe.org/5nfr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nfr RCSB], [http://www.ebi.ac.uk/pdbsum/5nfr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nfr ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5nfr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nfr OCA], [http://pdbe.org/5nfr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nfr RCSB], [http://www.ebi.ac.uk/pdbsum/5nfr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nfr ProSAT]</span></td></tr>
Line 17:		Line 18:
	</div>		</div>
	<div class="pdbe-citations 5nfr" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5nfr" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Malate dehydrogenase\|Malate dehydrogenase]]
	== References ==		== References ==
	<references/>		<references/>
Line 22:		Line 26:
	</StructureSection>		</StructureSection>
	[[Category: Malate dehydrogenase]]		[[Category: Malate dehydrogenase]]
		+	[[Category: Plaf7]]
	[[Category: Batista, F A]]		[[Category: Batista, F A]]
	[[Category: Groves, M R]]		[[Category: Groves, M R]]

OCA at 06:25, 9 May 2018

2018-05-09T06:25:53Z

←Older revision		Revision as of 06:25, 9 May 2018
Line 10:		Line 10:
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
-	~~The expression~~, ~~purification~~, ~~crystallization and preliminary X-ray diffraction characterization~~ of malate dehydrogenase ~~(MDH)~~ from ~~the malarial parasite~~ Plasmodium falciparum (PfMDH) ~~are reported~~. ~~In order to gain a deeper understanding~~ of the ~~function~~ and ~~role~~ of PfMDH, the ~~protein was purified to homogeneity. The purified protein crystallized~~ in ~~space group P1~~, ~~with unit~~-~~cell parameters a = 72~~, ~~b = 157~~, ~~c = 159 A~~, ~~alpha = 105, beta = 101, gamma = 95 degrees~~ . ~~The resulting crystals diffracted to a maximal resolution~~ of ~~2.24 A~~ and the ~~structure has been solved by molecular replacement~~, ~~with 16 monomers in~~ the ~~asymmetric unit~~. ~~The 16 monomers~~ are ~~arranged into four independent tetramers,~~ in ~~agreement with previous reports demonstrating~~ the ~~tetrameric solution state~~ of ~~PfMDH~~. ~~The X-ray structure of PfMDH is expected to clarify~~ the ~~differences~~ in ~~catalysis by PfMDH compared with other MDH family members and~~ to ~~provide a basis for the structure-based design~~ of ~~specific PfMDH inhibitors as well as general MDH inhibitors~~.	+	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.

-	~~Crystallization and preliminary X-ray diffraction~~ of malate dehydrogenase ~~from~~ Plasmodium falciparum.,~~Wrenger C, Muller IB~~, Butzloff S, ~~Jordanova R~~, ~~Lunev S~~, Groves MR ~~Acta Crystallogr Sect F Struct Biol Cryst Commun~~. ~~2012 Jun 1~~;68(~~Pt 6~~):~~659-62~~., doi: 10.~~1107~~/~~S1744309112014571~~. ~~Epub 2012 May 23~~. PMID:~~22684064~~<ref>PMID:~~22684064~~</ref>	+	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®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>

OCA at 05:49, 31 January 2018

2018-01-31T05:49:34Z

←Older revision		Revision as of 05:49, 31 January 2018
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5nfr is ~~ON HOLD~~	+	==Crystal structure of malate dehydrogenase from Plasmodium falciparum (PfMDH)==
		+	<StructureSection load='5nfr' size='340' side='right' caption='[[5nfr]], [[Resolution\|resolution]] 2.40Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5nfr]] is a 16 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NFR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NFR FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Malate_dehydrogenase Malate dehydrogenase], with EC number [http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5nfr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nfr OCA], [http://pdbe.org/5nfr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nfr RCSB], [http://www.ebi.ac.uk/pdbsum/5nfr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nfr ProSAT]</span></td></tr>
		+	</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The expression, purification, crystallization and preliminary X-ray diffraction characterization of malate dehydrogenase (MDH) from the malarial parasite Plasmodium falciparum (PfMDH) are reported. In order to gain a deeper understanding of the function and role of PfMDH, the protein was purified to homogeneity. The purified protein crystallized in space group P1, with unit-cell parameters a = 72, b = 157, c = 159 A, alpha = 105, beta = 101, gamma = 95 degrees . The resulting crystals diffracted to a maximal resolution of 2.24 A and the structure has been solved by molecular replacement, with 16 monomers in the asymmetric unit. The 16 monomers are arranged into four independent tetramers, in agreement with previous reports demonstrating the tetrameric solution state of PfMDH. The X-ray structure of PfMDH is expected to clarify the differences in catalysis by PfMDH compared with other MDH family members and to provide a basis for the structure-based design of specific PfMDH inhibitors as well as general MDH inhibitors.

-	~~Authors: Lunev~~, S., ~~Romero, A.~~R., ~~Batista~~, F.A., ~~Wrenger, C~~.~~, Groves, M~~.R.	+	Crystallization and preliminary X-ray diffraction of malate dehydrogenase from Plasmodium falciparum.,Wrenger C, Muller IB, Butzloff S, Jordanova R, Lunev S, Groves MR Acta Crystallogr Sect F Struct Biol Cryst Commun. 2012 Jun 1;68(Pt 6):659-62., doi: 10.1107/S1744309112014571. Epub 2012 May 23. PMID:22684064<ref>PMID:22684064</ref>

-	~~Description: Crystal structure~~ of ~~malate dehydrogenase from Plasmodium falciparum (PfMDH)~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
-	[[Category: Batista, F.A]]	+	<div class="pdbe-citations 5nfr" style="background-color:#fffaf0;"></div>
-	[[Category: ~~Wrenger~~, ~~C]]~~	+	== References ==
-	~~[[Category: Romero, A.~~R]]	+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Malate dehydrogenase]]
		+	[[Category: Batista, F A]]
		+	[[Category: Groves, M R]]
	[[Category: Lunev, S]]		[[Category: Lunev, S]]
-	[[Category: ~~Groves~~, M.R]]	+	[[Category: Romero, A R]]
		+	[[Category: Wrenger, C]]
		+	[[Category: Dehydrogenase]]
		+	[[Category: Malate metabolism]]
		+	[[Category: Oligomerisation]]
		+	[[Category: Oxidoreductase]]
		+	[[Category: Plasmodium falciparum]]

OCA: Protected "5nfr" [edit=sysop:move=sysop]

2017-04-05T10:03:38Z

Protected "5nfr" [edit=sysop:move=sysop]

←Older revision

Revision as of 10:03, 5 April 2017

OCA: New page: '''Unreleased structure''' The entry 5nfr is ON HOLD Authors: Lunev, S., Romero, A.R., Batista, F.A., Wrenger, C., Groves, M.R. Description: Crystal structure of malate dehydrogenase f...

2017-04-05T10:03:37Z

New page: '''Unreleased structure''' The entry 5nfr is ON HOLD Authors: Lunev, S., Romero, A.R., Batista, F.A., Wrenger, C., Groves, M.R. Description: Crystal structure of malate dehydrogenase f...

New page

'''Unreleased structure'''

The entry 5nfr is ON HOLD

Authors: Lunev, S., Romero, A.R., Batista, F.A., Wrenger, C., Groves, M.R.

Description: Crystal structure of malate dehydrogenase from Plasmodium falciparum (PfMDH)
[[Category: Unreleased Structures]]
[[Category: Batista, F.A]]
[[Category: Wrenger, C]]
[[Category: Romero, A.R]]
[[Category: Lunev, S]]
[[Category: Groves, M.R]]