1juj: Difference between revisions

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<StructureSection load='1juj' size='340' side='right'caption='[[1juj]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
<StructureSection load='1juj' size='340' side='right'caption='[[1juj]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1juj]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1JUJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1JUJ FirstGlance]. <br>
<table><tr><td colspan='2'>[[1juj]] is a 4 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=1JUJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1JUJ FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LYA:2-{4-[2-(2-AMINO-4-OXO-4,7-DIHYDRO-3H-PYRROLO[2,3-D]PYRIMIDIN-5-YL)-ETHYL]-BENZOYLAMINO}-PENTANEDIOIC+ACID'>LYA</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</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]] 3&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1jtq|1jtq]], [[1jtu|1jtu]], [[1ju6|1ju6]], [[1jut|1jut]]</div></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LYA:2-{4-[2-(2-AMINO-4-OXO-4,7-DIHYDRO-3H-PYRROLO[2,3-D]PYRIMIDIN-5-YL)-ETHYL]-BENZOYLAMINO}-PENTANEDIOIC+ACID'>LYA</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Thymidylate_synthase Thymidylate synthase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.45 2.1.1.45] </span></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=1juj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1juj OCA], [https://pdbe.org/1juj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1juj RCSB], [https://www.ebi.ac.uk/pdbsum/1juj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1juj ProSAT]</span></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=1juj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1juj OCA], [https://pdbe.org/1juj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1juj RCSB], [https://www.ebi.ac.uk/pdbsum/1juj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1juj ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[https://www.uniprot.org/uniprot/TYSY_HUMAN TYSY_HUMAN]] Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.<ref>PMID:21876188</ref>
[https://www.uniprot.org/uniprot/TYSY_HUMAN TYSY_HUMAN] Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.<ref>PMID:21876188</ref>  
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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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=1juj ConSurf].
</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=1juj ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Crystal structures of four pyrrolo(2,3-d)pyrimidine-based antifolate compounds, developed as inhibitors of thymidylate synthase (TS) in a strategy to circumvent drug-resistance, have been determined in complexes with their in vivo target, human thymidylate synthase, and with the structurally best-characterized Escherichia coli enzyme, to resolutions of 2.2-3.0 A. The 2.9 A crystal structure of a complex of human TS with one of the inhibitors, the multi-targeted antifolate LY231514, demonstrates that this compound induces a "closed" enzyme conformation and leads to formation of a covalent bond between enzyme and substrate. This structure is one of the first liganded human TS structures, and its solution was aided by mutation to facilitate crystallization. Structures of three other pyrrolo(2,3-d)pyrimidine-based antifolates in complex with Escherichia coli TS confirm the orientation of this class of inhibitors in the active site. Specific interactions between the polyglutamyl moiety and a positively charged groove on the enzyme surface explain the marked increase in affinity of the pyrrolo(2,3-d)pyrimidine inhibitors once they are polyglutamylated, as mediated in vivo by the cellular enzyme folyl polyglutamate synthetase.
Multi-targeted antifolates aimed at avoiding drug resistance form covalent closed inhibitory complexes with human and Escherichia coli thymidylate synthases.,Sayre PH, Finer-Moore JS, Fritz TA, Biermann D, Gates SB, MacKellar WC, Patel VF, Stroud RM J Mol Biol. 2001 Nov 2;313(4):813-29. PMID:11697906<ref>PMID:11697906</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1juj" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Thymidylate synthase]]
[[Category: Biermann D]]
[[Category: Biermann, D]]
[[Category: Finer-Moore JS]]
[[Category: Finer-Moore, J S]]
[[Category: Fritz TA]]
[[Category: Fritz, T A]]
[[Category: Gates SB]]
[[Category: Gates, S B]]
[[Category: MacKellar WC]]
[[Category: MacKellar, W C]]
[[Category: Patel VF]]
[[Category: Patel, V F]]
[[Category: Sayre PH]]
[[Category: Sayre, P H]]
[[Category: Stroud RM]]
[[Category: Stroud, R M]]
[[Category: Antifolate]]
[[Category: Cancer]]
[[Category: Drug resistance]]
[[Category: Dtmp synthesis]]
[[Category: Transferase]]

Revision as of 09:04, 3 April 2024

Human Thymidylate Synthase Bound to dUMP and LY231514, a Pyrrolo(2,3-d)pyrimidine-based AntifolateHuman Thymidylate Synthase Bound to dUMP and LY231514, a Pyrrolo(2,3-d)pyrimidine-based Antifolate

Structural highlights

1juj is a 4 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 3Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TYSY_HUMAN Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.[1]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

References

  1. ↑ Anderson DD, Quintero CM, Stover PJ. Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria. Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15163-8. doi:, 10.1073/pnas.1103623108. Epub 2011 Aug 26. PMID:21876188 doi:10.1073/pnas.1103623108

1juj, resolution 3.00Å

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