2pgr: Difference between revisions
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==Crystal structure of adenosine deaminase from Plasmodium vivax in complex with pentostatin== | |||
<StructureSection load='2pgr' size='340' side='right'caption='[[2pgr]], [[Resolution|resolution]] 2.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2pgr]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_vivax Plasmodium vivax]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2PGR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2PGR 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]] 2.3Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CCN:ACETONITRILE'>CCN</scene>, <scene name='pdbligand=DCF:2-DEOXYCOFORMYCIN'>DCF</scene>, <scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=2pgr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2pgr OCA], [https://pdbe.org/2pgr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2pgr RCSB], [https://www.ebi.ac.uk/pdbsum/2pgr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2pgr ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/ADA_PLAVS ADA_PLAVS] Catalyzes the hydrolytic deamination of adenosine to produce inosine (PubMed:19728741). Unlike mammalian adenosine deaminases, also catalyzes the deamination of 5'-methylthioadenosine (MTA), a by-product of polyamine biosynthesis, to produce 5'-methylthioinosine (MTI) (PubMed:19728741). Plays an essential role in the purine salvage pathway which allows the parasite to use host cell purines for the synthesis of nucleic acids (PubMed:19728741).<ref>PMID:19728741</ref> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/pg/2pgr_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2pgr ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Plasmodium and other apicomplexan parasites are deficient in purine biosynthesis, relying instead on the salvage of purines from their host environment. Therefore, interference with the purine salvage pathway is an attractive therapeutic target. The plasmodial enzyme adenosine deaminase (ADA) plays a central role in purine salvage and, unlike mammalian ADA homologs, has a further secondary role in methylthiopurine recycling. For this reason, plasmodial ADA accepts a wider range of substrates, as it is responsible for deamination of both adenosine and 5'-methylthioadenosine. The latter substrate is not accepted by mammalian ADA homologs. The structural basis for this natural difference in specificity between plasmodial and mammalian ADA has not been well understood. We now report crystal structures of Plasmodium vivax ADA in complex with adenosine, guanosine, and the picomolar inhibitor 2'-deoxycoformycin. These structures highlight a drastic conformational change in plasmodial ADA upon substrate binding that has not been observed for mammalian ADA enzymes. Further, these complexes illuminate the structural basis for the differential substrate specificity and potential drug selectivity between mammalian and parasite enzymes. | |||
Structures of substrate- and inhibitor-bound adenosine deaminase from a human malaria parasite show a dramatic conformational change and shed light on drug selectivity.,Larson ET, Deng W, Krumm BE, Napuli A, Mueller N, Van Voorhis WC, Buckner FS, Fan E, Lauricella A, DeTitta G, Luft J, Zucker F, Hol WG, Verlinde CL, Merritt EA J Mol Biol. 2008 Sep 12;381(4):975-88. Epub 2008 Jun 24. PMID:18602399<ref>PMID:18602399</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2pgr" style="background-color:#fffaf0;"></div> | |||
== | ==See Also== | ||
[[ | *[[Adenosine deaminase 3D structures|Adenosine deaminase 3D structures]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: Large Structures]] | |||
[[Category: Plasmodium vivax]] | [[Category: Plasmodium vivax]] | ||
[[Category: Larson | [[Category: Larson ET]] | ||
[[Category: Merritt | [[Category: Merritt EA]] | ||
Latest revision as of 11:28, 30 October 2024
Crystal structure of adenosine deaminase from Plasmodium vivax in complex with pentostatinCrystal structure of adenosine deaminase from Plasmodium vivax in complex with pentostatin
Structural highlights
FunctionADA_PLAVS Catalyzes the hydrolytic deamination of adenosine to produce inosine (PubMed:19728741). Unlike mammalian adenosine deaminases, also catalyzes the deamination of 5'-methylthioadenosine (MTA), a by-product of polyamine biosynthesis, to produce 5'-methylthioinosine (MTI) (PubMed:19728741). Plays an essential role in the purine salvage pathway which allows the parasite to use host cell purines for the synthesis of nucleic acids (PubMed:19728741).[1] 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 PubMedPlasmodium and other apicomplexan parasites are deficient in purine biosynthesis, relying instead on the salvage of purines from their host environment. Therefore, interference with the purine salvage pathway is an attractive therapeutic target. The plasmodial enzyme adenosine deaminase (ADA) plays a central role in purine salvage and, unlike mammalian ADA homologs, has a further secondary role in methylthiopurine recycling. For this reason, plasmodial ADA accepts a wider range of substrates, as it is responsible for deamination of both adenosine and 5'-methylthioadenosine. The latter substrate is not accepted by mammalian ADA homologs. The structural basis for this natural difference in specificity between plasmodial and mammalian ADA has not been well understood. We now report crystal structures of Plasmodium vivax ADA in complex with adenosine, guanosine, and the picomolar inhibitor 2'-deoxycoformycin. These structures highlight a drastic conformational change in plasmodial ADA upon substrate binding that has not been observed for mammalian ADA enzymes. Further, these complexes illuminate the structural basis for the differential substrate specificity and potential drug selectivity between mammalian and parasite enzymes. Structures of substrate- and inhibitor-bound adenosine deaminase from a human malaria parasite show a dramatic conformational change and shed light on drug selectivity.,Larson ET, Deng W, Krumm BE, Napuli A, Mueller N, Van Voorhis WC, Buckner FS, Fan E, Lauricella A, DeTitta G, Luft J, Zucker F, Hol WG, Verlinde CL, Merritt EA J Mol Biol. 2008 Sep 12;381(4):975-88. Epub 2008 Jun 24. PMID:18602399[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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