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2bsx

From Proteopedia

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Current revision

Crystal structure of the Plasmodium falciparum purine nucleoside phosphorylase complexed with inosine

Structural highlights

2bsx is a 1 chain structure with sequence from Plasmodium falciparum 3D7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 metabolism in the parasite Plasmodium has been identified as a promising target for antimalarial therapies. Purine nucleoside phosphorylase (PNP) is part of a salvage pathway for the biosynthesis of purines, which are essential for parasite survival. Two crystal structures of PNP from Plasmodium falciparum (PfPNP) in two space groups, each with a single subunit in the asymmetric unit, are described here. One structure, refined to 2.4 A, has an empty nucleoside-binding site and a sulfate ion bound in the phosphate-binding pocket. The second structure, refined to 2.0 A, has the substrate inosine bound to the active centre. Structure comparison reveals alterations in the active site upon ligand binding. The new structures presented here specifically highlight the likely roles of Asp206 and two loops flanking the active site: the beta7-alpha6 loop (residues approximately 161-169) and the beta9-alpha8 loop (residues approximately 208-223). Comparison with PNP in complex with transition-state inhibitors suggests that the purine substrate moves towards the phosphate substrate, rather than vice versa, upon forming the transition state. The single-substrate-containing PfPNP structures also appear to be more flexible than PfPNP bound to inhibitors. Together, these structures serve as a basis for better understanding of ligand binding and mechanism that can be further exploited to optimize the specificity of anti-PfPNP drugs.

Structures of Plasmodium falciparum purine nucleoside phosphorylase complexed with sulfate and its natural substrate inosine.,Schnick C, Robien MA, Brzozowski AM, Dodson EJ, Murshudov GN, Anderson L, Luft JR, Mehlin C, Hol WG, Brannigan JA, Wilkinson AJ Acta Crystallogr D Biol Crystallogr. 2005 Sep;61(Pt 9):1245-54. Epub 2005, Aug 16. PMID:16131758^[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
↑ 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

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2bsx"

@@ Line 3: / Line 3: @@
 <StructureSection load='2bsx' size='340' side='right'caption='[[2bsx]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2bsx]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Plaf7 Plaf7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2BSX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2BSX FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2bsx]] is a 1 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=2BSX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2BSX FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NOS:INOSINE'>NOS</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]] 2&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Purine-nucleoside_phosphorylase Purine-nucleoside phosphorylase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.1 2.4.2.1] </span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NOS:INOSINE'>NOS</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=2bsx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2bsx OCA], [https://pdbe.org/2bsx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2bsx RCSB], [https://www.ebi.ac.uk/pdbsum/2bsx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2bsx 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]]
@@ Line 35: / Line 37: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Plaf7]]
+[[Category: Plasmodium falciparum 3D7]]
-[[Category: Purine-nucleoside phosphorylase]]
+[[Category: Brannigan JA]]
-[[Category: Brannigan, J A]]
+[[Category: Brzozowski AM]]
-[[Category: Brzozowski, A M]]
+[[Category: Dodson EJ]]
-[[Category: Dodson, E J]]
+[[Category: Murshudov GN]]
-[[Category: Murshudov, G N]]
+[[Category: Schnick C]]
-[[Category: Schnick, C]]
+[[Category: Wilkinson AJ]]
-[[Category: Wilkinson, A J]]
-[[Category: Glycosyltransferase]]
-[[Category: Purine nucleoside phosphorylase]]
-[[Category: Putative]]
-[[Category: Transferase]]
-[[Category: Uridine phosphorylase]]

2bsx

From Proteopedia

Current revision

Crystal structure of the Plasmodium falciparum purine nucleoside phosphorylase complexed with inosine

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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