6smw: Difference between revisions
New page: '''Unreleased structure''' The entry 6smw is ON HOLD Authors: Ruszkowski, M., Sekula, B., Dauter, Z. Description: A. thaliana serine hydroxymethyltransferase isoform 2 (AtSHMT2) in com... |
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==A. thaliana serine hydroxymethyltransferase isoform 2 (AtSHMT2) in complex with pemetrexed== | |||
<StructureSection load='6smw' size='340' side='right'caption='[[6smw]], [[Resolution|resolution]] 1.54Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6smw]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Arabidopsis_thaliana Arabidopsis thaliana]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6SMW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6SMW 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]] 1.54Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <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=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene>, <scene name='pdbligand=PLS:[3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YLMETHYL]-SERINE'>PLS</scene>, <scene name='pdbligand=SER:SERINE'>SER</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=6smw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6smw OCA], [https://pdbe.org/6smw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6smw RCSB], [https://www.ebi.ac.uk/pdbsum/6smw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6smw ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/GLYM2_ARATH GLYM2_ARATH] Functions outside the photorespiratory pathway in catalyzing the interconversion of serine and glycine.<ref>PMID:16339799</ref> <ref>PMID:21976482</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Serine hydroxymethyltransferases (SHMTs) reversibly transform serine into glycine in a reaction accompanied with conversion of tetrahydrofolate (THF) into 5,10-methylene-THF (5,10-meTHF). In vivo, 5,10-meTHF is the main carrier of one-carbon (1C) units, which are utilized for nucleotide biosynthesis and other processes crucial for every living cell, but hyperactivated in overproliferating cells (e.g. cancer tissues). SHMTs are emerging as a promising target for development of new drugs because it appears possible to inhibit growth of cancer cells by cutting off the supply of 5,10-meTHF. Methotrexate (MTX) and pemetrexed (PTX) are two examples of antifolates that have cured many patients over the years but target different enzymes from the folate cycle (mainly dihydrofolate reductase and thymidylate synthase, respectively). Here we show crystal structures of MTX and PTX bound to plant SHMT isozymes from cytosol and mitochondria-human isozymes exist in the same subcellular compartments. We verify inhibition of the studied isozymes by a thorough kinetic analysis. We propose to further exploit antifolate scaffold in development of SHMT inhibitors because it seems likely that especially polyglutamylated PTX inhibits SHMTs in vivo. Structure-based optimization is expected to yield novel antifolates that could potentially be used as chemotherapeutics. | |||
Structural basis of methotrexate and pemetrexed action on serine hydroxymethyltransferases revealed using plant models.,Ruszkowski M, Sekula B, Ruszkowska A, Contestabile R, Nogues I, Angelaccio S, Szczepaniak A, Dauter Z Sci Rep. 2019 Dec 23;9(1):19614. doi: 10.1038/s41598-019-56043-4. PMID:31873125<ref>PMID:31873125</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6smw" style="background-color:#fffaf0;"></div> | ||
[[Category: Ruszkowski | |||
[[Category: | ==See Also== | ||
*[[Serine hydroxymethyltransferase 3D structures|Serine hydroxymethyltransferase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Arabidopsis thaliana]] | |||
[[Category: Large Structures]] | |||
[[Category: Dauter Z]] | |||
[[Category: Ruszkowski M]] | |||
[[Category: Sekula B]] | |||
Latest revision as of 15:44, 24 January 2024
A. thaliana serine hydroxymethyltransferase isoform 2 (AtSHMT2) in complex with pemetrexedA. thaliana serine hydroxymethyltransferase isoform 2 (AtSHMT2) in complex with pemetrexed
Structural highlights
FunctionGLYM2_ARATH Functions outside the photorespiratory pathway in catalyzing the interconversion of serine and glycine.[1] [2] Publication Abstract from PubMedSerine hydroxymethyltransferases (SHMTs) reversibly transform serine into glycine in a reaction accompanied with conversion of tetrahydrofolate (THF) into 5,10-methylene-THF (5,10-meTHF). In vivo, 5,10-meTHF is the main carrier of one-carbon (1C) units, which are utilized for nucleotide biosynthesis and other processes crucial for every living cell, but hyperactivated in overproliferating cells (e.g. cancer tissues). SHMTs are emerging as a promising target for development of new drugs because it appears possible to inhibit growth of cancer cells by cutting off the supply of 5,10-meTHF. Methotrexate (MTX) and pemetrexed (PTX) are two examples of antifolates that have cured many patients over the years but target different enzymes from the folate cycle (mainly dihydrofolate reductase and thymidylate synthase, respectively). Here we show crystal structures of MTX and PTX bound to plant SHMT isozymes from cytosol and mitochondria-human isozymes exist in the same subcellular compartments. We verify inhibition of the studied isozymes by a thorough kinetic analysis. We propose to further exploit antifolate scaffold in development of SHMT inhibitors because it seems likely that especially polyglutamylated PTX inhibits SHMTs in vivo. Structure-based optimization is expected to yield novel antifolates that could potentially be used as chemotherapeutics. Structural basis of methotrexate and pemetrexed action on serine hydroxymethyltransferases revealed using plant models.,Ruszkowski M, Sekula B, Ruszkowska A, Contestabile R, Nogues I, Angelaccio S, Szczepaniak A, Dauter Z Sci Rep. 2019 Dec 23;9(1):19614. doi: 10.1038/s41598-019-56043-4. PMID:31873125[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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