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| - | [[Image:1q1g.gif|left|200px]]<br /><applet load="1q1g" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1q1g, resolution 2.02Å" /> | |
| - | '''Crystal structure of Plasmodium falciparum PNP with 5'-methylthio-immucillin-H'''<br /> | |
| | | | |
| - | ==Overview== | + | ==Crystal structure of Plasmodium falciparum PNP with 5'-methylthio-immucillin-H== |
| - | Purine nucleoside phosphorylase from Plasmodium falciparum (PfPNP) is an, anti-malarial target based on the activity of Immucillins. The crystal, structure of PfPNP.Immucillin-H (ImmH).SO(4) reveals a homohexamer with, ImmH and SO(4) bound at each catalytic site. A solvent-filled cavity close, to the 5'-hydroxyl group of ImmH suggested that PfPNP can accept, additional functional groups at the 5'-carbon. Assays established, 5'-methylthioinosine (MTI) as a substrate for PfPNP. MTI is not found in, human metabolism. These properties of PfPNP suggest unusual purine, pathways in P. falciparum and provide structural and mechanistic, foundations for the design of malaria-specific transition state analogue, inhibitors. 5'-Methylthio-Immucillin-H (MT-ImmH) was designed to resemble, the transition state of PfPNP and binds to PfPNP and human-PNP with K(d), values of 2.7 and 303 nm, respectively, to give a discrimination factor of, 112. MT-ImmH is the first inhibitor that favors PfPNP inhibition. The, structure of PfPNP.MT-ImmH.SO(4) shows that the hydrophobic methylthio, group inserts into a hydrophobic region adjacent to the more hydrophilic, 5'-hydroxyl binding site of ImmH. The catalytic features of PfPNP indicate, a dual cellular function in purine salvage and polyamine metabolism., Combined metabolic functions in a single enzyme strengthen the rationale, for targeting PfPNP in anti-malarial action. | + | <StructureSection load='1q1g' size='340' side='right'caption='[[1q1g]], [[Resolution|resolution]] 2.02Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[1q1g]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Q1G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1Q1G 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]] 2.02Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=MTI:3,4-DIHYDROXY-2-[(METHYLSULFANYL)METHYL]-5-(4-OXO-4,5-DIHYDRO-3H-PYRROLO[3,2-D]PYRIMIDIN-7-YL)PYRROLIDINIUM'>MTI</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=1q1g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1q1g OCA], [https://pdbe.org/1q1g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1q1g RCSB], [https://www.ebi.ac.uk/pdbsum/1q1g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1q1g ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/PNPH_PLAF7 PNPH_PLAF7] 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:18957439, PubMed:14982926, PubMed:16131758, PubMed:19575810, PubMed:24416224, PubMed:29440412). Preferentially acts on inosine and guanosine, and to a lesser extent on 2'-deoxyguanosine and guanosine (PubMed:14982926, PubMed:16131758, PubMed:19575810). Also catalyzes the phosphorylation of S-methyl-5'-thioinosine (MTI) to hypoxanthine; MTI is produced by adenosine deaminase (ADA)-mediated breakdown of S-methyl-5'-thioadenosine (MTA), a major by-product of polyamine biosynthesis (PubMed:18957439, PubMed:14982926, PubMed:24416224). Generates hypoxanthine from both the purine salvage pathway and from polyamine metabolism which is required for nucleic acids synthesis (PubMed:18957439, PubMed:14982926, PubMed:24416224). Has no activity towards adenosine (By similarity).[UniProtKB:Q8T9Z7]<ref>PMID:14982926</ref> <ref>PMID:16131758</ref> <ref>PMID:18957439</ref> <ref>PMID:19575810</ref> <ref>PMID:24416224</ref> <ref>PMID:29440412</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/q1/1q1g_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.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=1q1g ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Purine nucleoside phosphorylase from Plasmodium falciparum (PfPNP) is an anti-malarial target based on the activity of Immucillins. The crystal structure of PfPNP.Immucillin-H (ImmH).SO(4) reveals a homohexamer with ImmH and SO(4) bound at each catalytic site. A solvent-filled cavity close to the 5'-hydroxyl group of ImmH suggested that PfPNP can accept additional functional groups at the 5'-carbon. Assays established 5'-methylthioinosine (MTI) as a substrate for PfPNP. MTI is not found in human metabolism. These properties of PfPNP suggest unusual purine pathways in P. falciparum and provide structural and mechanistic foundations for the design of malaria-specific transition state analogue inhibitors. 5'-Methylthio-Immucillin-H (MT-ImmH) was designed to resemble the transition state of PfPNP and binds to PfPNP and human-PNP with K(d) values of 2.7 and 303 nm, respectively, to give a discrimination factor of 112. MT-ImmH is the first inhibitor that favors PfPNP inhibition. The structure of PfPNP.MT-ImmH.SO(4) shows that the hydrophobic methylthio group inserts into a hydrophobic region adjacent to the more hydrophilic 5'-hydroxyl binding site of ImmH. The catalytic features of PfPNP indicate a dual cellular function in purine salvage and polyamine metabolism. Combined metabolic functions in a single enzyme strengthen the rationale for targeting PfPNP in anti-malarial action. |
| | | | |
| - | ==About this Structure==
| + | Plasmodium falciparum purine nucleoside phosphorylase: crystal structures, immucillin inhibitors, and dual catalytic function.,Shi W, Ting LM, Kicska GA, Lewandowicz A, Tyler PC, Evans GB, Furneaux RH, Kim K, Almo SC, Schramm VL J Biol Chem. 2004 Apr 30;279(18):18103-6. Epub 2004 Feb 23. PMID:14982926<ref>PMID:14982926</ref> |
| - | 1Q1G is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Plasmodium_falciparum_3d7 Plasmodium falciparum 3d7] with SO4, MTI and IPA as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Purine-nucleoside_phosphorylase Purine-nucleoside phosphorylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.1 2.4.2.1] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1Q1G OCA].
| + | |
| | | | |
| - | ==Reference==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | Plasmodium falciparum purine nucleoside phosphorylase: crystal structures, immucillin inhibitors, and dual catalytic function., Shi W, Ting LM, Kicska GA, Lewandowicz A, Tyler PC, Evans GB, Furneaux RH, Kim K, Almo SC, Schramm VL, J Biol Chem. 2004 Apr 30;279(18):18103-6. Epub 2004 Feb 23. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=14982926 14982926]
| + | </div> |
| - | [[Category: Plasmodium falciparum 3d7]]
| + | <div class="pdbe-citations 1q1g" style="background-color:#fffaf0;"></div> |
| - | [[Category: Purine-nucleoside phosphorylase]] | + | == References == |
| - | [[Category: Single protein]] | + | <references/> |
| - | [[Category: Almo, S.C.]] | + | __TOC__ |
| - | [[Category: Evans, G.B.]] | + | </StructureSection> |
| - | [[Category: Furneaux, R.H.]] | + | [[Category: Large Structures]] |
| - | [[Category: Kicska, G.A.]] | + | [[Category: Plasmodium falciparum 3D7]] |
| - | [[Category: Kim, K.]] | + | [[Category: Almo SC]] |
| - | [[Category: Lewandowicz, A.]] | + | [[Category: Evans GB]] |
| - | [[Category: Schramm, V.L.]] | + | [[Category: Furneaux RH]] |
| - | [[Category: Shi, W.]] | + | [[Category: Kicska GA]] |
| - | [[Category: Ting, L.M.]] | + | [[Category: Kim K]] |
| - | [[Category: Tyler, P.C.]] | + | [[Category: Lewandowicz A]] |
| - | [[Category: IPA]]
| + | [[Category: Schramm VL]] |
| - | [[Category: MTI]]
| + | [[Category: Shi W]] |
| - | [[Category: SO4]]
| + | [[Category: Ting LM]] |
| - | [[Category: transition state complex]]
| + | [[Category: Tyler PC]] |
| - | | + | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Sun Nov 25 03:23:58 2007''
| + | |
| Structural highlights
Function
PNPH_PLAF7 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:18957439, PubMed:14982926, PubMed:16131758, PubMed:19575810, PubMed:24416224, PubMed:29440412). Preferentially acts on inosine and guanosine, and to a lesser extent on 2'-deoxyguanosine and guanosine (PubMed:14982926, PubMed:16131758, PubMed:19575810). Also catalyzes the phosphorylation of S-methyl-5'-thioinosine (MTI) to hypoxanthine; MTI is produced by adenosine deaminase (ADA)-mediated breakdown of S-methyl-5'-thioadenosine (MTA), a major by-product of polyamine biosynthesis (PubMed:18957439, PubMed:14982926, PubMed:24416224). Generates hypoxanthine from both the purine salvage pathway and from polyamine metabolism which is required for nucleic acids synthesis (PubMed:18957439, PubMed:14982926, PubMed:24416224). Has no activity towards adenosine (By similarity).[UniProtKB:Q8T9Z7][1] [2] [3] [4] [5] [6]
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
Purine nucleoside phosphorylase from Plasmodium falciparum (PfPNP) is an anti-malarial target based on the activity of Immucillins. The crystal structure of PfPNP.Immucillin-H (ImmH).SO(4) reveals a homohexamer with ImmH and SO(4) bound at each catalytic site. A solvent-filled cavity close to the 5'-hydroxyl group of ImmH suggested that PfPNP can accept additional functional groups at the 5'-carbon. Assays established 5'-methylthioinosine (MTI) as a substrate for PfPNP. MTI is not found in human metabolism. These properties of PfPNP suggest unusual purine pathways in P. falciparum and provide structural and mechanistic foundations for the design of malaria-specific transition state analogue inhibitors. 5'-Methylthio-Immucillin-H (MT-ImmH) was designed to resemble the transition state of PfPNP and binds to PfPNP and human-PNP with K(d) values of 2.7 and 303 nm, respectively, to give a discrimination factor of 112. MT-ImmH is the first inhibitor that favors PfPNP inhibition. The structure of PfPNP.MT-ImmH.SO(4) shows that the hydrophobic methylthio group inserts into a hydrophobic region adjacent to the more hydrophilic 5'-hydroxyl binding site of ImmH. The catalytic features of PfPNP indicate a dual cellular function in purine salvage and polyamine metabolism. Combined metabolic functions in a single enzyme strengthen the rationale for targeting PfPNP in anti-malarial action.
Plasmodium falciparum purine nucleoside phosphorylase: crystal structures, immucillin inhibitors, and dual catalytic function.,Shi W, Ting LM, Kicska GA, Lewandowicz A, Tyler PC, Evans GB, Furneaux RH, Kim K, Almo SC, Schramm VL J Biol Chem. 2004 Apr 30;279(18):18103-6. Epub 2004 Feb 23. PMID:14982926[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Shi W, Ting LM, Kicska GA, Lewandowicz A, Tyler PC, Evans GB, Furneaux RH, Kim K, Almo SC, Schramm VL. Plasmodium falciparum purine nucleoside phosphorylase: crystal structures, immucillin inhibitors, and dual catalytic function. J Biol Chem. 2004 Apr 30;279(18):18103-6. Epub 2004 Feb 23. PMID:14982926 doi:10.1074/jbc.C400068200
- ↑ Schnick C, Robien MA, Brzozowski AM, Dodson EJ, Murshudov GN, Anderson L, Luft JR, Mehlin C, Hol WG, Brannigan JA, Wilkinson AJ. Structures of Plasmodium falciparum purine nucleoside phosphorylase complexed with sulfate and its natural substrate inosine. Acta Crystallogr D Biol Crystallogr. 2005 Sep;61(Pt 9):1245-54. Epub 2005, Aug 16. PMID:16131758 doi:10.1107/S0907444905020251
- ↑ Madrid DC, Ting LM, Waller KL, Schramm VL, Kim K. Plasmodium falciparum purine nucleoside phosphorylase is critical for viability of malaria parasites. J Biol Chem. 2008 Dec 19;283(51):35899-907. doi: 10.1074/jbc.M807218200. Epub, 2008 Oct 28. PMID:18957439 doi:http://dx.doi.org/10.1074/jbc.M807218200
- ↑ Chaikuad A, Brady RL. Conservation of structure and activity in Plasmodium purine nucleoside phosphorylases. BMC Struct Biol. 2009 Jul 3;9:42. PMID:19575810 doi:10.1186/1472-6807-9-42
- ↑ Donaldson TM, Ting LM, Zhan C, Shi W, Zheng R, Almo SC, Kim K. Structural determinants of the 5'-methylthioinosine specificity of Plasmodium purine nucleoside phosphorylase. PLoS One. 2014 Jan 8;9(1):e84384. doi: 10.1371/journal.pone.0084384. eCollection , 2014. PMID:24416224 doi:http://dx.doi.org/10.1371/journal.pone.0084384
- ↑ Ducati RG, Namanja-Magliano HA, Harijan RK, Fajardo JE, Fiser A, Daily JP, Schramm VL. Genetic resistance to purine nucleoside phosphorylase inhibition in Plasmodium falciparum. Proc Natl Acad Sci U S A. 2018 Feb 12. pii: 1525670115. doi:, 10.1073/pnas.1525670115. PMID:29440412 doi:http://dx.doi.org/10.1073/pnas.1525670115
- ↑ Shi W, Ting LM, Kicska GA, Lewandowicz A, Tyler PC, Evans GB, Furneaux RH, Kim K, Almo SC, Schramm VL. Plasmodium falciparum purine nucleoside phosphorylase: crystal structures, immucillin inhibitors, and dual catalytic function. J Biol Chem. 2004 Apr 30;279(18):18103-6. Epub 2004 Feb 23. PMID:14982926 doi:10.1074/jbc.C400068200
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