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| | ==Crystal structure of pteridine reductase 1 (PTR1) from Trypanosoma brucei in ternary complex with cofactor (NADP+) and inhibitor 1,3,5-triazine-2,4,6-triamine (AX2)== | | ==Crystal structure of pteridine reductase 1 (PTR1) from Trypanosoma brucei in ternary complex with cofactor (NADP+) and inhibitor 1,3,5-triazine-2,4,6-triamine (AX2)== |
| - | <StructureSection load='3jqf' size='340' side='right' caption='[[3jqf]], [[Resolution|resolution]] 1.60Å' scene=''> | + | <StructureSection load='3jqf' size='340' side='right'caption='[[3jqf]], [[Resolution|resolution]] 1.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3jqf]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Trypanosoma_(trypanozoon)_brucei Trypanosoma (trypanozoon) brucei]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=3bmm 3bmm]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3JQF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3JQF FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3jqf]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_brucei Trypanosoma brucei]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=3bmm 3bmm]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3JQF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3JQF FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=AX2:1,3,5-TRIAZINE-2,4,6-TRIAMINE'>AX2</scene>, <scene name='pdbligand=D1D:(4S,5S)-1,2-DITHIANE-4,5-DIOL'>D1D</scene>, <scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</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]] 1.6Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CSX:S-OXY+CYSTEINE'>CSX</scene></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=AX2:1,3,5-TRIAZINE-2,4,6-TRIAMINE'>AX2</scene>, <scene name='pdbligand=CSX:S-OXY+CYSTEINE'>CSX</scene>, <scene name='pdbligand=D1D:(4S,5S)-1,2-DITHIANE-4,5-DIOL'>D1D</scene>, <scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3jq6|3jq6]], [[3jq7|3jq7]], [[3jq8|3jq8]], [[3jq9|3jq9]], [[3jqa|3jqa]], [[3jqb|3jqb]], [[3jqc|3jqc]], [[3jqd|3jqd]], [[3jqe|3jqe]], [[3jqg|3jqg]]</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=3jqf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3jqf OCA], [https://pdbe.org/3jqf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3jqf RCSB], [https://www.ebi.ac.uk/pdbsum/3jqf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3jqf ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PTR1, Tb927.8.2210 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5691 Trypanosoma (Trypanozoon) brucei])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Pteridine_reductase Pteridine reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.33 1.5.1.33] </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=3jqf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3jqf OCA], [http://pdbe.org/3jqf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3jqf RCSB], [http://www.ebi.ac.uk/pdbsum/3jqf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3jqf ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/Q581W1_TRYB2 Q581W1_TRYB2] |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Pteridine reductase]] | + | [[Category: Large Structures]] |
| - | [[Category: Hunter, W N]]
| + | |
| - | [[Category: Tulloch, L B]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Ptr1]]
| + | |
| - | [[Category: Short chain dehydrogenase]]
| + | |
| | [[Category: Trypanosoma brucei]] | | [[Category: Trypanosoma brucei]] |
| | + | [[Category: Hunter WN]] |
| | + | [[Category: Tulloch LB]] |
| Structural highlights
3jqf is a 4 chain structure with sequence from Trypanosoma brucei. This structure supersedes the now removed PDB entry 3bmm. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.6Å |
| Ligands: | , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
Q581W1_TRYB2
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Pteridine reductase (PTR1) is a target for drug development against Trypanosoma and Leishmania species, parasites that cause serious tropical diseases and for which therapies are inadequate. We adopted a structure-based approach to the design of novel PTR1 inhibitors based on three molecular scaffolds. A series of compounds, most newly synthesized, were identified as inhibitors with PTR1-species specific properties explained by structural differences between the T. brucei and L. major enzymes. The most potent inhibitors target T. brucei PTR1, and two compounds displayed antiparasite activity against the bloodstream form of the parasite. PTR1 contributes to antifolate drug resistance by providing a molecular bypass of dihydrofolate reductase (DHFR) inhibition. Therefore, combining PTR1 and DHFR inhibitors might improve therapeutic efficacy. We tested two new compounds with known DHFR inhibitors. A synergistic effect was observed for one particular combination highlighting the potential of such an approach for treatment of African sleeping sickness.
Structure-Based Design of Pteridine Reductase Inhibitors Targeting African Sleeping Sickness and the Leishmaniases.,Tulloch LB, Martini VP, Iulek J, Huggan JK, Lee JH, Gibson CL, Smith TK, Suckling CJ, Hunter WN J Med Chem. 2009 Nov 16. PMID:19916554[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Tulloch LB, Martini VP, Iulek J, Huggan JK, Lee JH, Gibson CL, Smith TK, Suckling CJ, Hunter WN. Structure-Based Design of Pteridine Reductase Inhibitors Targeting African Sleeping Sickness and the Leishmaniases. J Med Chem. 2009 Nov 16. PMID:19916554 doi:10.1021/jm901059x
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