3c39: Difference between revisions

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[[Image:3c39.png|left|200px]]


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==Crystal Structure of human phosphoglycerate kinase bound to 3-phosphoglycerate==
The line below this paragraph, containing "STRUCTURE_3c39", creates the "Structure Box" on the page.
<StructureSection load='3c39' size='340' side='right'caption='[[3c39]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
You may change the PDB parameter (which sets the PDB file loaded into the applet)
== Structural highlights ==
or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
<table><tr><td colspan='2'>[[3c39]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3C39 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3C39 FirstGlance]. <br>
or leave the SCENE parameter empty for the default display.
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.85&#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=3PG:3-PHOSPHOGLYCERIC+ACID'>3PG</scene></td></tr>
{{STRUCTURE_3c39|  PDB=3c39  |  SCENE=  }}
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3c39 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3c39 OCA], [https://pdbe.org/3c39 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3c39 RCSB], [https://www.ebi.ac.uk/pdbsum/3c39 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3c39 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/PGK1_HUMAN PGK1_HUMAN] Defects in PGK1 are the cause of phosphoglycerate kinase 1 deficiency (PGK1D) [MIM:[https://omim.org/entry/300653 300653]. It is a condition with a highly variable clinical phenotype that includes hemolytic anemia, rhabdomyolysis, myopathy and neurologic involvement. Patients can express one or more of these manifestations.<ref>PMID:8673469</ref> <ref>PMID:8043870</ref> <ref>PMID:8615693</ref> <ref>PMID:9744480</ref> <ref>PMID:2001457</ref> <ref>PMID:1586722</ref> <ref>PMID:1547346</ref> <ref>PMID:6941312</ref> <ref>PMID:6933565</ref>
== Function ==
[https://www.uniprot.org/uniprot/PGK1_HUMAN PGK1_HUMAN] In addition to its role as a glycolytic enzyme, it seems that PGK-1 acts as a polymerase alpha cofactor protein (primer recognition protein).
== 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/c3/3c39_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=3c39 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Non-natural L-nucleoside analogues are increasingly used as therapeutic agents to treat cancer and viral infections. To be active, L-nucleosides need to be phosphorylated to their respective triphosphate metabolites. This stepwise phosphorylation relies on human enzymes capable of processing L-nucleoside enantiomers. We used crystallographic analysis to reveal the molecular basis for the low enantioselectivity and the broad specificity of human 3-phosphoglycerate kinase (hPGK), an enzyme responsible for the last step of phosphorylation of many nucleotide derivatives. Based on structures of hPGK in the absence of nucleotides, and bound to L and d forms of MgADP and MgCDP, we show that a non-specific hydrophobic clamp to the nucleotide base, as well as a water-filled cavity behind it, allows high flexibility in the interaction between PGK and the bases. This, combined with the dispensability of hydrogen bonds to the sugar moiety, and ionic interactions with the phosphate groups, results in the positioning of different nucleotides so to expose their diphosphate group in a position competent for catalysis. Since the third phosphorylation step is often rate limiting, our results are expected to alleviate in silico tailoring of L-type prodrugs to assure their efficient metabolic processing.


===Crystal Structure of human phosphoglycerate kinase bound to 3-phosphoglycerate===
Molecular basis for the lack of enantioselectivity of human 3-phosphoglycerate kinase.,Gondeau C, Chaloin L, Lallemand P, Roy B, Perigaud C, Barman T, Varga A, Vas M, Lionne C, Arold ST Nucleic Acids Res. 2008 Jun;36(11):3620-9. Epub 2008 May 7. PMID:18463139<ref>PMID:18463139</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3c39" style="background-color:#fffaf0;"></div>


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==See Also==
The line below this paragraph, {{ABSTRACT_PUBMED_18463139}}, adds the Publication Abstract to the page
*[[Phosphoglycerate kinase 3D structures|Phosphoglycerate kinase 3D structures]]
(as it appears on PubMed at http://www.pubmed.gov), where 18463139 is the PubMed ID number.
== References ==
-->
<references/>
{{ABSTRACT_PUBMED_18463139}}
__TOC__
 
</StructureSection>
==Disease==
Known disease associated with this structure: Phosphoglycerate kinase 1 deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=311800 311800]]
 
==About this Structure==
3C39 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3C39 OCA].
 
==Reference==
Molecular basis for the lack of enantioselectivity of human 3-phosphoglycerate kinase., Gondeau C, Chaloin L, Lallemand P, Roy B, Perigaud C, Barman T, Varga A, Vas M, Lionne C, Arold ST, Nucleic Acids Res. 2008 Jun;36(11):3620-9. Epub 2008 May 7. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18463139 18463139]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Phosphoglycerate kinase]]
[[Category: Large Structures]]
[[Category: Single protein]]
[[Category: Arold ST]]
[[Category: Arold, S T.]]
[[Category: Chaloin L]]
[[Category: Chaloin, L.]]
[[Category: Gondeau C]]
[[Category: Gondeau, C.]]
[[Category: Lionne C]]
[[Category: Lionne, C.]]
[[Category: Acetylation]]
[[Category: Atp-binding]]
[[Category: Beta sandwich]]
[[Category: Cytoplasm]]
[[Category: Disease mutation]]
[[Category: Glycolysis]]
[[Category: Hereditary hemolytic anemia]]
[[Category: Kinase]]
[[Category: Nucleotide-binding]]
[[Category: Phosphoprotein]]
[[Category: Polymorphism]]
[[Category: Transferase]]
[[Category: Two domain]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 09:30:21 2008''

Latest revision as of 17:54, 1 November 2023

Crystal Structure of human phosphoglycerate kinase bound to 3-phosphoglycerateCrystal Structure of human phosphoglycerate kinase bound to 3-phosphoglycerate

Structural highlights

3c39 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.85Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PGK1_HUMAN Defects in PGK1 are the cause of phosphoglycerate kinase 1 deficiency (PGK1D) [MIM:300653. It is a condition with a highly variable clinical phenotype that includes hemolytic anemia, rhabdomyolysis, myopathy and neurologic involvement. Patients can express one or more of these manifestations.[1] [2] [3] [4] [5] [6] [7] [8] [9]

Function

PGK1_HUMAN In addition to its role as a glycolytic enzyme, it seems that PGK-1 acts as a polymerase alpha cofactor protein (primer recognition protein).

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

Non-natural L-nucleoside analogues are increasingly used as therapeutic agents to treat cancer and viral infections. To be active, L-nucleosides need to be phosphorylated to their respective triphosphate metabolites. This stepwise phosphorylation relies on human enzymes capable of processing L-nucleoside enantiomers. We used crystallographic analysis to reveal the molecular basis for the low enantioselectivity and the broad specificity of human 3-phosphoglycerate kinase (hPGK), an enzyme responsible for the last step of phosphorylation of many nucleotide derivatives. Based on structures of hPGK in the absence of nucleotides, and bound to L and d forms of MgADP and MgCDP, we show that a non-specific hydrophobic clamp to the nucleotide base, as well as a water-filled cavity behind it, allows high flexibility in the interaction between PGK and the bases. This, combined with the dispensability of hydrogen bonds to the sugar moiety, and ionic interactions with the phosphate groups, results in the positioning of different nucleotides so to expose their diphosphate group in a position competent for catalysis. Since the third phosphorylation step is often rate limiting, our results are expected to alleviate in silico tailoring of L-type prodrugs to assure their efficient metabolic processing.

Molecular basis for the lack of enantioselectivity of human 3-phosphoglycerate kinase.,Gondeau C, Chaloin L, Lallemand P, Roy B, Perigaud C, Barman T, Varga A, Vas M, Lionne C, Arold ST Nucleic Acids Res. 2008 Jun;36(11):3620-9. Epub 2008 May 7. PMID:18463139[10]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Yoshida A, Twele TW, Dave V, Beutler E. Molecular abnormality of a phosphoglycerate kinase variant (PGK-Alabama). Blood Cells Mol Dis. 1995;21(3):179-81. PMID:8673469 doi:S1079-9796(85)70020-4
  2. ↑ Cohen-Solal M, Valentin C, Plassa F, Guillemin G, Danze F, Jaisson F, Rosa R. Identification of new mutations in two phosphoglycerate kinase (PGK) variants expressing different clinical syndromes: PGK Creteil and PGK Amiens. Blood. 1994 Aug 1;84(3):898-903. PMID:8043870
  3. ↑ Ookawara T, Dave V, Willems P, Martin JJ, de Barsy T, Matthys E, Yoshida A. Retarded and aberrant splicings caused by single exon mutation in a phosphoglycerate kinase variant. Arch Biochem Biophys. 1996 Mar 1;327(1):35-40. PMID:8615693 doi:http://dx.doi.org/10.1006/abbi.1996.0089
  4. ↑ Valentin C, Birgens H, Craescu CT, Brodum-Nielsen K, Cohen-Solal M. A phosphoglycerate kinase mutant (PGK Herlev; D285V) in a Danish patient with isolated chronic hemolytic anemia: mechanism of mutation and structure-function relationships. Hum Mutat. 1998;12(4):280-7. PMID:9744480 doi:<280::AID-HUMU10>3.0.CO;2-V 10.1002/(SICI)1098-1004(1998)12:4<280::AID-HUMU10>3.0.CO;2-V
  5. ↑ Maeda M, Yoshida A. Molecular defect of a phosphoglycerate kinase variant (PGK-Matsue) associated with hemolytic anemia: Leu----Pro substitution caused by T/A----C/G transition in exon 3. Blood. 1991 Mar 15;77(6):1348-52. PMID:2001457
  6. ↑ Maeda M, Bawle EV, Kulkarni R, Beutler E, Yoshida A. Molecular abnormalities of a phosphoglycerate kinase variant generated by spontaneous mutation. Blood. 1992 May 15;79(10):2759-62. PMID:1586722
  7. ↑ Fujii H, Kanno H, Hirono A, Shiomura T, Miwa S. A single amino acid substitution (157 Gly----Val) in a phosphoglycerate kinase variant (PGK Shizuoka) associated with chronic hemolysis and myoglobinuria. Blood. 1992 Mar 15;79(6):1582-5. PMID:1547346
  8. ↑ Fujii H, Chen SH, Akatsuka J, Miwa S, Yoshida A. Use of cultured lymphoblastoid cells for the study of abnormal enzymes: molecular abnormality of a phosphoglycerate kinase variant associated with hemolytic anemia. Proc Natl Acad Sci U S A. 1981 Apr;78(4):2587-90. PMID:6941312
  9. ↑ Fujii H, Yoshida A. Molecular abnormality of phosphoglycerate kinase-Uppsala associated with chronic nonspherocytic hemolytic anemia. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5461-5. PMID:6933565
  10. ↑ Gondeau C, Chaloin L, Lallemand P, Roy B, Perigaud C, Barman T, Varga A, Vas M, Lionne C, Arold ST. Molecular basis for the lack of enantioselectivity of human 3-phosphoglycerate kinase. Nucleic Acids Res. 2008 Jun;36(11):3620-9. Epub 2008 May 7. PMID:18463139 doi:10.1093/nar/gkn212

3c39, resolution 1.85Å

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