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| | <StructureSection load='6smn' size='340' side='right'caption='[[6smn]], [[Resolution|resolution]] 1.63Å' scene=''> | | <StructureSection load='6smn' size='340' side='right'caption='[[6smn]], [[Resolution|resolution]] 1.63Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6smn]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6SMN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6SMN FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6smn]] 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=6SMN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6SMN FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MTX:METHOTREXATE'>MTX</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> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.63Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=LLP:(2S)-2-AMINO-6-[[3-HYDROXY-2-METHYL-5-(PHOSPHONOOXYMETHYL)PYRIDIN-4-YL]METHYLIDENEAMINO]HEXANOIC+ACID'>LLP</scene></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=LLP:(2S)-2-AMINO-6-[[3-HYDROXY-2-METHYL-5-(PHOSPHONOOXYMETHYL)PYRIDIN-4-YL]METHYLIDENEAMINO]HEXANOIC+ACID'>LLP</scene>, <scene name='pdbligand=MTX:METHOTREXATE'>MTX</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='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glycine_hydroxymethyltransferase Glycine hydroxymethyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.2.1 2.1.2.1] </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=6smn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6smn OCA], [https://pdbe.org/6smn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6smn RCSB], [https://www.ebi.ac.uk/pdbsum/6smn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6smn ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6smn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6smn OCA], [http://pdbe.org/6smn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6smn RCSB], [http://www.ebi.ac.uk/pdbsum/6smn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6smn ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6smn" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6smn" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Serine hydroxymethyltransferase 3D structures|Serine hydroxymethyltransferase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Glycine hydroxymethyltransferase]] | + | [[Category: Arabidopsis thaliana]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Dauter, Z]] | + | [[Category: Dauter Z]] |
| - | [[Category: Ruszkowski, M]] | + | [[Category: Ruszkowski M]] |
| - | [[Category: Sekula, B]] | + | [[Category: Sekula B]] |
| - | [[Category: Antifolate]]
| + | |
| - | [[Category: Shmt]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
6smn is a 4 chain structure with sequence from Arabidopsis thaliana. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.63Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
GLYM2_ARATH Functions outside the photorespiratory pathway in catalyzing the interconversion of serine and glycine.[1] [2]
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[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Voll LM, Jamai A, Renne P, Voll H, McClung CR, Weber AP. The photorespiratory Arabidopsis shm1 mutant is deficient in SHM1. Plant Physiol. 2006 Jan;140(1):59-66. doi: 10.1104/pp.105.071399. Epub 2005 Dec, 9. PMID:16339799 doi:http://dx.doi.org/10.1104/pp.105.071399
- ↑ Engel N, Ewald R, Gupta KJ, Zrenner R, Hagemann M, Bauwe H. The presequence of Arabidopsis serine hydroxymethyltransferase SHM2 selectively prevents import into mesophyll mitochondria. Plant Physiol. 2011 Dec;157(4):1711-20. doi: 10.1104/pp.111.184564. Epub 2011 Oct, 5. PMID:21976482 doi:http://dx.doi.org/10.1104/pp.111.184564
- ↑ Ruszkowski M, Sekula B, Ruszkowska A, Contestabile R, Nogues I, Angelaccio S, Szczepaniak A, Dauter Z. Structural basis of methotrexate and pemetrexed action on serine hydroxymethyltransferases revealed using plant models. Sci Rep. 2019 Dec 23;9(1):19614. doi: 10.1038/s41598-019-56043-4. PMID:31873125 doi:http://dx.doi.org/10.1038/s41598-019-56043-4
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