4yv0: Difference between revisions

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-'''Unreleased structure'''
-The entry 4yv0 is ON HOLD  until Paper Publication
+==Crystal structure of Trypanosoma cruzi spermidine synthase in complex with (2S)-N-methyl-N-phenyl-2,3-dihydro-1,4-benzodioxine- 2-carboxamid==
+<StructureSection load='4yv0' size='340' side='right'caption='[[4yv0]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4yv0]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_cruzi_strain_CL_Brener Trypanosoma cruzi strain CL Brener]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YV0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4YV0 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]] 1.95&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4JW:(2S)-N-METHYL-N-PHENYL-2,3-DIHYDRO-1,4-BENZODIOXINE-2-CARBOXAMIDE'>4JW</scene>, <scene name='pdbligand=S4M:5-[(S)-(3-AMINOPROPYL)(METHYL)-LAMBDA~4~-SULFANYL]-5-DEOXYADENOSINE'>S4M</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=4yv0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yv0 OCA], [https://pdbe.org/4yv0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4yv0 RCSB], [https://www.ebi.ac.uk/pdbsum/4yv0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4yv0 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/Q4DA73_TRYCC Q4DA73_TRYCC]
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Trypanosoma cruzi causes Chagas disease, a severe disease affecting 8-10 million people in Latin America. While nifurtimox and benznidazole are used to treat this disease, their efficacy is limited and adverse effects are observed. New therapeutic targets and novel drugs are therefore urgently required. Enzymes in the polyamine-trypanothione pathway are promising targets for the treatment of Chagas disease. Spermidine synthase is a key enzyme in this pathway that catalyzes the transfer of an aminopropyl group from decarboxylated S-adenosylmethionine (dcSAM) to putrescine. Fragment-based drug discovery was therefore conducted to identify novel, potent inhibitors of spermidine synthase from T. cruzi (TcSpdSyn). Here, crystal structures of TcSpdSyn in complex with dcSAM, trans-4-methylcyclohexylamine and hit compounds from fragment screening are reported. The structure of dcSAM complexed with TcSpdSyn indicates that dcSAM stabilizes the conformation of the `gatekeeping' loop to form the putrescine-binding pocket. The structures of fragments bound to TcSpdSyn revealed two fragment-binding sites: the putrescine-binding pocket and the dimer interface. The putrescine-binding pocket was extended by an induced-fit mechanism. The crystal structures indicate that the conformation of the dimer interface is required to stabilize the gatekeeping loop and that fragments binding to this interface inhibit TcSpdSyn by disrupting its conformation. These results suggest that utilizing the dynamic structural changes in TcSpdSyn that occur upon inhibitor binding will facilitate the development of more selective and potent inhibitors.
-Authors: Amano, Y., Tateishi, Y.
+Structural insights into the novel inhibition mechanism of Trypanosoma cruzi spermidine synthase.,Amano Y, Namatame I, Tateishi Y, Honboh K, Tanabe E, Niimi T, Sakashita H Acta Crystallogr D Biol Crystallogr. 2015 Sep;71(Pt 9):1879-89. doi:, 10.1107/S1399004715013048. Epub 2015 Aug 25. PMID:26327378<ref>PMID:26327378</ref>
-Description: Crystal structure of Trypanosoma cruzi spermidine synthase in complex with trans-4-methylcyclohexylamine
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Amano, Y]]
+<div class="pdbe-citations 4yv0" style="background-color:#fffaf0;"></div>
-[[Category: Tateishi, Y]]
+==See Also==
+*[[Spermidine synthase 3D structures|Spermidine synthase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
+[[Category: Trypanosoma cruzi strain CL Brener]]
+[[Category: Amano Y]]
+[[Category: Tateishi Y]]