2wpf: Difference between revisions

Latest revision as of 10:13, 20 December 2023

Trypanosoma brucei trypanothione reductase in complex with 3,4- dihydroquinazoline inhibitor (DDD00085762)

Structural highlights

2wpf is a 4 chain structure with sequence from Trypanosoma brucei brucei TREU927. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.9Å
Ligands:	BR, CL, FAD, WPF
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

Q389T8_TRYB2

Publication Abstract from PubMed

Trypanothione reductase (TryR) is a genetically validated drug target in the parasite Trypanosoma brucei , the causative agent of human African trypanosomiasis. Here we report the discovery, synthesis, and development of a novel series of TryR inhibitors based on a 3,4-dihydroquinazoline scaffold. In addition, a high resolution crystal structure of TryR, alone and in complex with substrates and inhibitors from this series, is presented. This represents the first report of a high resolution complex between a noncovalent ligand and this enzyme. Structural studies revealed that upon ligand binding the enzyme undergoes a conformational change to create a new subpocket which is occupied by an aryl group on the ligand. Therefore, the inhibitor, in effect, creates its own small binding pocket within the otherwise large, solvent exposed active site. The TryR-ligand structure was subsequently used to guide the synthesis of inhibitors, including analogues that challenged the induced subpocket. This resulted in the development of inhibitors with improved potency against both TryR and T. brucei parasites in a whole cell assay.

Dihydroquinazolines as a Novel Class of Trypanosoma brucei Trypanothione Reductase Inhibitors: Discovery, Synthesis, and Characterization of their Binding Mode by Protein Crystallography.,Patterson S, Alphey MS, Jones DC, Shanks EJ, Street IP, Frearson JA, Wyatt PG, Gilbert IH, Fairlamb AH J Med Chem. 2011 Oct 13;54(19):6514-30. Epub 2011 Sep 1. PMID:21851087^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Patterson S, Alphey MS, Jones DC, Shanks EJ, Street IP, Frearson JA, Wyatt PG, Gilbert IH, Fairlamb AH. Dihydroquinazolines as a Novel Class of Trypanosoma brucei Trypanothione Reductase Inhibitors: Discovery, Synthesis, and Characterization of their Binding Mode by Protein Crystallography. J Med Chem. 2011 Oct 13;54(19):6514-30. Epub 2011 Sep 1. PMID:21851087 doi:10.1021/jm200312v

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Patterson S, Alphey MS, Jones DC, Shanks EJ, Street IP, Frearson JA, Wyatt PG, Gilbert IH, Fairlamb AH. Dihydroquinazolines as a Novel Class of Trypanosoma brucei Trypanothione Reductase Inhibitors: Discovery, Synthesis, and Characterization of their Binding Mode by Protein Crystallography. J Med Chem. 2011 Oct 13;54(19):6514-30. Epub 2011 Sep 1. PMID:21851087 doi:10.1021/jm200312v

[1]

@@ Line 1: / Line 1: @@
-==TRYPANOSOMA BRUCEI TRYPANOTHIONE REDUCTASE IN COMPLEX WITH 3,4-DIHYDROQUINAZOLINE INHIBITOR (DDD00085762)==
+==Trypanosoma brucei trypanothione reductase in complex with 3,4- dihydroquinazoline inhibitor (DDD00085762)==
-<StructureSection load='2wpf' size='340' side='right' caption='[[2wpf]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
+<StructureSection load='2wpf' size='340' side='right'caption='[[2wpf]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2wpf]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Trypanosoma_brucei_treu927 Trypanosoma brucei treu927]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2WPF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2WPF FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2wpf]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_brucei_brucei_TREU927 Trypanosoma brucei brucei TREU927]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2WPF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2WPF FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BR:BROMIDE+ION'>BR</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=WPF:3-[(4S)-6-CHLORO-2-METHYL-4-(4-METHYLPHENYL)QUINAZOLIN-3(4H)-YL]-N,N-DIMETHYLPROPAN-1-AMINE'>WPF</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]] 1.9&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2wov|2wov]], [[2wp6|2wp6]], [[2wpe|2wpe]], [[2wp5|2wp5]], [[2wpc|2wpc]], [[2woi|2woi]], [[2wow|2wow]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BR:BROMIDE+ION'>BR</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=WPF:3-[(4S)-6-CHLORO-2-METHYL-4-(4-METHYLPHENYL)QUINAZOLIN-3(4H)-YL]-N,N-DIMETHYLPROPAN-1-AMINE'>WPF</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Trypanothione-disulfide_reductase Trypanothione-disulfide reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.8.1.12 1.8.1.12] </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=2wpf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wpf OCA], [https://pdbe.org/2wpf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2wpf RCSB], [https://www.ebi.ac.uk/pdbsum/2wpf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2wpf 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=2wpf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wpf OCA], [http://pdbe.org/2wpf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2wpf RCSB], [http://www.ebi.ac.uk/pdbsum/2wpf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2wpf ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/TYTR_TRYBB TYTR_TRYBB]] Trypanothione is the parasite analog of glutathione; this enzyme is the equivalent of glutathione reductase.
+[https://www.uniprot.org/uniprot/Q389T8_TRYB2 Q389T8_TRYB2]
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 27: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Trypanosoma brucei treu927]]
+[[Category: Large Structures]]
-[[Category: Trypanothione-disulfide reductase]]
+[[Category: Trypanosoma brucei brucei TREU927]]
-[[Category: Alphey, M S]]
+[[Category: Alphey MS]]
-[[Category: Fairlamb, A H]]
+[[Category: Fairlamb AH]]
-[[Category: Patterson, S]]
+[[Category: Patterson S]]
-[[Category: Flavoprotein]]
-[[Category: Oxidoreductase]]
-[[Category: Redox-active center]]
-[[Category: Sleeping sickness]]
-[[Category: Trypanosomiasis]]

2wpf: Difference between revisions

Latest revision as of 10:13, 20 December 2023

Trypanosoma brucei trypanothione reductase in complex with 3,4- dihydroquinazoline inhibitor (DDD00085762)

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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