2p4s

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[[Image:2p4s.jpg|left|200px]]
 
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==Structure of Purine Nucleoside Phosphorylase from Anopheles gambiae in complex with DADMe-ImmH==
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The line below this paragraph, containing "STRUCTURE_2p4s", creates the "Structure Box" on the page.
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<StructureSection load='2p4s' size='340' side='right'caption='[[2p4s]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[2p4s]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Anopheles_gambiae Anopheles gambiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2P4S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2P4S FirstGlance]. <br>
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or leave the SCENE parameter empty for the default display.
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DIH:3-HYDROXY-4-HYDROXYMETHYL-1-(4-OXO-4,4A,5,7A-TETRAHYDRO-3H-PYRROLO[3,2-D]PYRIMIDIN-7-YLMETHYL)-PYRROLIDINIUM'>DIH</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
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{{STRUCTURE_2p4s| PDB=2p4s | SCENE= }}
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2p4s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2p4s OCA], [https://pdbe.org/2p4s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2p4s RCSB], [https://www.ebi.ac.uk/pdbsum/2p4s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2p4s ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/PNPH_ANOGA PNPH_ANOGA] As part of the purine salvage pathway, catalyzes the phosphorolytic breakdown of the N-glycosidic bond in the beta-(deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate (PubMed:17918964). Preferentially acts on 2'-deoxyinosine and inosine, and to a lesser extent on 2'-deoxyguanosine and guanosine (PubMed:17918964). Has no activity towards adenosine or 2'-deoxyadenosine (PubMed:17918964).<ref>PMID:17918964</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/p4/2p4s_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=2p4s ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The purine salvage pathway of Anopheles gambiae, a mosquito that transmits malaria, has been identified in genome searches on the basis of sequence homology with characterized enzymes. Purine nucleoside phosphorylase (PNP) is a target for the development of therapeutic agents in humans and purine auxotrophs, including malarial parasites. The PNP from Anopheles gambiae (AgPNP) was expressed in Escherichia coli and compared to the PNPs from Homo sapiens (HsPNP) and Plasmodium falciparum (PfPNP). AgPNP has kcat values of 54 and 41 s-1 for 2'-deoxyinosine and inosine, its preferred substrates, and 1.0 s-1 for guanosine. However, the chemical step is fast for AgPNP at 226 s-1 for guanosine in pre-steady-state studies. 5'-Deaza-1'-aza-2'-deoxy-1'-(9-methylene)-Immucillin-H (DADMe-ImmH) is a transition-state mimic for a 2'-deoxyinosine ribocation with a fully dissociated N-ribosidic bond and is a slow-onset, tight-binding inhibitor with a dissociation constant of 3.5 pM. This is the tightest-binding inhibitor known for any PNP, with a remarkable Km/Ki* of 5.4 x 10(7), and is consistent with enzymatic transition state predictions of enhanced transition-state analogue binding in enzymes with enhanced catalytic efficiency. Deoxyguanosine is a weaker substrate than deoxyinosine, and DADMe-Immucillin-G is less tightly bound than DADMe-ImmH, with a dissociation constant of 23 pM for AgPNP as compared to 7 pM for HsPNP. The crystal structure of AgPNP was determined in complex with DADMe-ImmH and phosphate to a resolution of 2.2 A to reveal the differences in substrate and inhibitor specificity. The distance from the N1' cation to the phosphate O4 anion is shorter in the AgPNP.DADMe-ImmH.PO4 complex than in HsPNP.DADMe-ImmH.SO4, offering one explanation for the stronger inhibitory effect of DADMe-ImmH for AgPNP.
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'''Structure of Purine Nucleoside Phosphorylase from Anopheles gambiae in complex with DADMe-ImmH'''
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Anopheles gambiae purine nucleoside phosphorylase: catalysis, structure, and inhibition.,Taylor EA, Rinaldo-Matthis A, Li L, Ghanem M, Hazleton KZ, Cassera MB, Almo SC, Schramm VL Biochemistry. 2007 Oct 30;46(43):12405-15. Epub 2007 Oct 6. PMID:17918964<ref>PMID:17918964</ref>
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==Overview==
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The purine salvage pathway of Anopheles gambiae, a mosquito that transmits malaria, has been identified in genome searches on the basis of sequence homology with characterized enzymes. Purine nucleoside phosphorylase (PNP) is a target for the development of therapeutic agents in humans and purine auxotrophs, including malarial parasites. The PNP from Anopheles gambiae (AgPNP) was expressed in Escherichia coli and compared to the PNPs from Homo sapiens (HsPNP) and Plasmodium falciparum (PfPNP). AgPNP has kcat values of 54 and 41 s-1 for 2'-deoxyinosine and inosine, its preferred substrates, and 1.0 s-1 for guanosine. However, the chemical step is fast for AgPNP at 226 s-1 for guanosine in pre-steady-state studies. 5'-Deaza-1'-aza-2'-deoxy-1'-(9-methylene)-Immucillin-H (DADMe-ImmH) is a transition-state mimic for a 2'-deoxyinosine ribocation with a fully dissociated N-ribosidic bond and is a slow-onset, tight-binding inhibitor with a dissociation constant of 3.5 pM. This is the tightest-binding inhibitor known for any PNP, with a remarkable Km/Ki* of 5.4 x 10(7), and is consistent with enzymatic transition state predictions of enhanced transition-state analogue binding in enzymes with enhanced catalytic efficiency. Deoxyguanosine is a weaker substrate than deoxyinosine, and DADMe-Immucillin-G is less tightly bound than DADMe-ImmH, with a dissociation constant of 23 pM for AgPNP as compared to 7 pM for HsPNP. The crystal structure of AgPNP was determined in complex with DADMe-ImmH and phosphate to a resolution of 2.2 A to reveal the differences in substrate and inhibitor specificity. The distance from the N1' cation to the phosphate O4 anion is shorter in the AgPNP.DADMe-ImmH.PO4 complex than in HsPNP.DADMe-ImmH.SO4, offering one explanation for the stronger inhibitory effect of DADMe-ImmH for AgPNP.
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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2P4S is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Anopheles_gambiae Anopheles gambiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2P4S OCA].
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</div>
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<div class="pdbe-citations 2p4s" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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Anopheles gambiae purine nucleoside phosphorylase: catalysis, structure, and inhibition., Taylor EA, Rinaldo-Matthis A, Li L, Ghanem M, Hazleton KZ, Cassera MB, Almo SC, Schramm VL, Biochemistry. 2007 Oct 30;46(43):12405-15. Epub 2007 Oct 6. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17918964 17918964]
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*[[Purine nucleoside phosphorylase 3D structures|Purine nucleoside phosphorylase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Anopheles gambiae]]
[[Category: Anopheles gambiae]]
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[[Category: Purine-nucleoside phosphorylase]]
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[[Category: Large Structures]]
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[[Category: Single protein]]
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[[Category: Almo SC]]
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[[Category: Almo, S C.]]
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[[Category: Rinaldo-Matthis A]]
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[[Category: Rinaldo-Matthis, A.]]
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[[Category: Schramm VL]]
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[[Category: Schramm, V L.]]
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[[Category: Purine nucleoside phosphorylase]]
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[[Category: Transferase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 12:21:34 2008''
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Current revision

Structure of Purine Nucleoside Phosphorylase from Anopheles gambiae in complex with DADMe-ImmH

PDB ID 2p4s

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