OCA at 12:22, 7 November 2018

2018-11-07T12:22:32Z

←Older revision		Revision as of 12:22, 7 November 2018
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-	'''Unreleased structure'''

-	~~The entry~~ 6hjg is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Trypanosoma cruzi proline racemase in complex with inhibitor OxoPA==
		+	<StructureSection load='6hjg' size='340' side='right' caption='[[6hjg]], [[Resolution\|resolution]] 1.90Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6hjg]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HJG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HJG FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SHF:LAEVULINIC+ACID'>SHF</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1w61\|1w61]]</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Proline_racemase Proline racemase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.1.1.4 5.1.1.4] </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=6hjg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hjg OCA], [http://pdbe.org/6hjg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6hjg RCSB], [http://www.ebi.ac.uk/pdbsum/6hjg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6hjg ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/PRCMA_TRYCC PRCMA_TRYCC]] Catalyzes the interconversion of L- and D-proline. Secreted isoform 1 contributes to parasite immune evasion by acting as a B-cell mitogen. Probably involved in parasite differentiation and infectivity.<ref>PMID:10932226</ref> <ref>PMID:16164548</ref> <ref>PMID:16446443</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Chagas disease, caused by Trypanosoma cruzi, affects millions of people in South America and no satisfactory therapy exists, especially for its life threatening chronic phase. We targeted the Proline Racemase of T. cruzi, which is present in all stages of the parasite life cycle, to discover new inhibitors against this disease. The first published crystal structures of the enzyme revealed that the catalytic site is too small to allow any relevant drug design. In previous work, to break through the chemical space afforded to virtual screening and drug design, we generated intermediate models between the open (ligand free) and closed (ligand bound) forms of the enzyme. In the present work, we co-crystallized the enzyme with the selected inhibitors and found that they were covalently bound to the catalytic cysteine residues in the active site, thus explaining why these compounds act as irreversible inhibitors. These results led us to the design of a novel, more potent specific inhibitor, NG-P27. Co-crystallization of this new inhibitor with the enzyme allowed us to confirm the predicted protein functional motions and further characterize the chemical mechanism. Hence, the catalytic Cys300 sulfur atom of the enzyme attacks the C2 carbon of the inhibitor in a coupled, regiospecific-stereospecific Michael reaction with trans-addition of a proton on the C3 carbon. Strikingly, the six different conformations of the catalytic site in the crystal structures reported in this work had key similarities to our intermediate models previously genrated by inference of the protein functional motions. These crystal structures span a conformational interval covering roughly the first quarter of the opening mechanism, demonstrating the relevance of modeling approaches to break through chemical space in drug design.

-	~~Authors: Saul~~, F., Haouz, A., Uriac, P., Blondel, A., Minoprio, P.	+	Designed mono- and di-covalent inhibitors trap modeled functional motions for Trypanosoma cruzi proline racemase in crystallography.,Amaral PA, Autheman D, de Melo GD, Gouault N, Cupif JF, Goyard S, Dutra P, Coatnoan N, Cosson A, Monet D, Saul F, Haouz A, Uriac P, Blondel A, Minoprio P PLoS Negl Trop Dis. 2018 Oct 29;12(10):e0006853. doi:, 10.1371/journal.pntd.0006853. PMID:30372428<ref>PMID:30372428</ref>

-	~~Description: Trypanosoma cruzi proline racemase in complex with inhibitor OxoPA~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[Category: Unreleased Structures]]~~	+	</div>
-	~~[[Category~~: ~~Saul, F]]~~	+	<div class="pdbe-citations 6hjg" style="background-color:#fffaf0;"></div>
-	[[Category: ~~Minoprio, P~~]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Proline racemase]]
	[[Category: Blondel, A]]		[[Category: Blondel, A]]
-	[[Category: Uriac, P]]
	[[Category: Haouz, A]]		[[Category: Haouz, A]]
		+	[[Category: Minoprio, P]]
		+	[[Category: Saul, F]]
		+	[[Category: Uriac, P]]
		+	[[Category: Drug design]]
		+	[[Category: Isomerase]]
		+	[[Category: Michael reaction]]

OCA at 06:09, 26 September 2018

2018-09-26T06:09:26Z

←Older revision		Revision as of 06:09, 26 September 2018
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6hjg is ON HOLD	+	The entry 6hjg is ON HOLD until Paper Publication

	Authors: Saul, F., Haouz, A., Uriac, P., Blondel, A., Minoprio, P.		Authors: Saul, F., Haouz, A., Uriac, P., Blondel, A., Minoprio, P.
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	Description: Trypanosoma cruzi proline racemase in complex with inhibitor OxoPA		Description: Trypanosoma cruzi proline racemase in complex with inhibitor OxoPA
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Uriac, P]]
	[[Category: Saul, F]]		[[Category: Saul, F]]
	[[Category: Minoprio, P]]		[[Category: Minoprio, P]]
	[[Category: Blondel, A]]		[[Category: Blondel, A]]
		+	[[Category: Uriac, P]]
	[[Category: Haouz, A]]		[[Category: Haouz, A]]

OCA: Protected "6hjg" [edit=sysop:move=sysop]

2018-09-12T06:03:59Z

Protected "6hjg" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:03, 12 September 2018

OCA: New page: '''Unreleased structure''' The entry 6hjg is ON HOLD Authors: Saul, F., Haouz, A., Uriac, P., Blondel, A., Minoprio, P. Description: Trypanosoma cruzi proline racemase in complex with ...

2018-09-12T06:03:57Z

New page: '''Unreleased structure''' The entry 6hjg is ON HOLD Authors: Saul, F., Haouz, A., Uriac, P., Blondel, A., Minoprio, P. Description: Trypanosoma cruzi proline racemase in complex with ...

New page

'''Unreleased structure'''

The entry 6hjg is ON HOLD

Authors: Saul, F., Haouz, A., Uriac, P., Blondel, A., Minoprio, P.

Description: Trypanosoma cruzi proline racemase in complex with inhibitor OxoPA
[[Category: Unreleased Structures]]
[[Category: Uriac, P]]
[[Category: Saul, F]]
[[Category: Minoprio, P]]
[[Category: Blondel, A]]
[[Category: Haouz, A]]

6hjg - Revision history

OCA at 12:22, 7 November 2018

OCA at 06:09, 26 September 2018

OCA: Protected "6hjg" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 6hjg is ON HOLD Authors: Saul, F., Haouz, A., Uriac, P., Blondel, A., Minoprio, P. Description: Trypanosoma cruzi proline racemase in complex with ...