2c7v: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2c7v]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Trypanosoma_brucei_brucei Trypanosoma brucei brucei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2C7V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2C7V FirstGlance]. <br> | <table><tr><td colspan='2'>[[2c7v]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Trypanosoma_brucei_brucei Trypanosoma brucei brucei]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2C7V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2C7V FirstGlance]. <br> | ||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=MTX:METHOTREXATE'>MTX</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>< | </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=MTX:METHOTREXATE'>MTX</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene></td></tr> | ||
<tr><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CAF:S-DIMETHYLARSINOYL-CYSTEINE'>CAF</scene></td></tr> | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CAF:S-DIMETHYLARSINOYL-CYSTEINE'>CAF</scene></td></tr> | ||
<tr><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='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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2c7v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2c7v OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2c7v RCSB], [http://www.ebi.ac.uk/pdbsum/2c7v PDBsum]</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=2c7v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2c7v OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2c7v RCSB], [http://www.ebi.ac.uk/pdbsum/2c7v PDBsum]</span></td></tr> | ||
<table> | </table> | ||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
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[[Category: Pteridine reductase]] | [[Category: Pteridine reductase]] | ||
[[Category: Trypanosoma brucei brucei]] | [[Category: Trypanosoma brucei brucei]] | ||
[[Category: Dawson, A | [[Category: Dawson, A]] | ||
[[Category: Fairlamb, A H | [[Category: Fairlamb, A H]] | ||
[[Category: Fyfe, P K | [[Category: Fyfe, P K]] | ||
[[Category: Gibellini, F | [[Category: Gibellini, F]] | ||
[[Category: Hunter, W N | [[Category: Hunter, W N]] | ||
[[Category: Mcluskey, K | [[Category: Mcluskey, K]] | ||
[[Category: Sienkiewicz, N | [[Category: Sienkiewicz, N]] | ||
[[Category: Drug resistance]] | [[Category: Drug resistance]] | ||
[[Category: Methotrexate resistance]] | [[Category: Methotrexate resistance]] | ||
[[Category: Oxidoreductase]] | [[Category: Oxidoreductase]] | ||
[[Category: Short-chain dehydrogenase/reductase]] | [[Category: Short-chain dehydrogenase/reductase]] | ||
[[Category: Trypanosomatid]] | [[Category: Trypanosomatid]] | ||
Revision as of 20:23, 15 January 2015
STRUCTURE OF TRYPANOSOMA BRUCEI PTERIDINE REDUCTASE (PTR1) IN TERNARY COMPLEX WITH COFACTOR AND THE ANTIFOLATE METHOTREXATESTRUCTURE OF TRYPANOSOMA BRUCEI PTERIDINE REDUCTASE (PTR1) IN TERNARY COMPLEX WITH COFACTOR AND THE ANTIFOLATE METHOTREXATE
Structural highlights
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 PubMedThe protozoan Trypanosoma brucei has a functional pteridine reductase (TbPTR1), an NADPH-dependent short-chain reductase that participates in the salvage of pterins, which are essential for parasite growth. PTR1 displays broad-spectrum activity with pterins and folates, provides a metabolic bypass for inhibition of the trypanosomatid dihydrofolate reductase and therefore compromises the use of antifolates for treatment of trypanosomiasis. Catalytic properties of recombinant TbPTR1 and inhibition by the archetypal antifolate methotrexate have been characterized and the crystal structure of the ternary complex with cofactor NADP+ and the inhibitor determined at 2.2 A resolution. This enzyme shares 50% amino acid sequence identity with Leishmania major PTR1 (LmPTR1) and comparisons show that the architecture of the cofactor binding site, and the catalytic centre are highly conserved, as are most interactions with the inhibitor. However, specific amino acid differences, in particular the placement of Trp221 at the side of the active site, and adjustment of the beta6-alpha6 loop and alpha6 helix at one side of the substrate-binding cleft significantly reduce the size of the substrate binding site of TbPTR1 and alter the chemical properties compared with LmPTR1. A reactive Cys168, within the active site cleft, in conjunction with the C-terminus carboxyl group and His267 of a partner subunit forms a triad similar to the catalytic component of cysteine proteases. TbPTR1 therefore offers novel structural features to exploit in the search for inhibitors of therapeutic value against African trypanosomiasis. Structure and reactivity of Trypanosoma brucei pteridine reductase: inhibition by the archetypal antifolate methotrexate.,Dawson A, Gibellini F, Sienkiewicz N, Tulloch LB, Fyfe PK, McLuskey K, Fairlamb AH, Hunter WN Mol Microbiol. 2006 Sep;61(6):1457-68. PMID:16968221[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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