7qei: Difference between revisions
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==Structure of human MTHFD2L in complex with TH7299== | |||
<StructureSection load='7qei' size='340' side='right'caption='[[7qei]], [[Resolution|resolution]] 2.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7qei]] is a 1 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=7QEI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QEI 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]] 2.1Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9L9:(2S)-2-[[4-[[2,4-BIS(AZANYL)-6-OXIDANYLIDENE-1H-PYRIMIDIN-5-YL]CARBAMOYLAMINO]PHENYL]CARBONYLAMINO]PENTANEDIOIC+ACID'>9L9</scene>, <scene name='pdbligand=ATR:2-MONOPHOSPHOADENOSINE-5-DIPHOSPHATE'>ATR</scene>, <scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</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=7qei FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qei OCA], [https://pdbe.org/7qei PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qei RCSB], [https://www.ebi.ac.uk/pdbsum/7qei PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qei ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/MTD2L_HUMAN MTD2L_HUMAN] Bifunctional mitochondrial folate-interconverting enzyme that has both NAD/NADP-dependent methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities.[UniProtKB:D3ZUA0] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial 1-carbon metabolism enzyme, which is an attractive anticancer drug target as it is highly upregulated in cancer but is not expressed in healthy adult cells. Selective MTHFD2 inhibitors could therefore offer reduced side-effects during treatment, which are common with antifolate drugs that target other 1C-metabolism enzymes. This task is challenging however, as MTHFD2 shares high sequence identity with the constitutively expressed isozymes cytosolic MTHFD1 and mitochondrial MTHFD2L. In fact, one of the most potent MTHFD2 inhibitors reported to date, TH7299, is actually more active against MTHFD1 and MTHFD2L. While structures of MTHFD2 and MTHFD1 exist, no MTHFD2L structures are available. We determined the first structure of MTHFD2L and its complex with TH7299, which reveals the structural basis for its highly potent MTHFD2L inhibition. Detailed analysis of the MTHFD2L structure presented here clearly highlights the challenges associated with developing truly isoform-selective MTHFD2 inhibitors. | |||
The First Structure of Human MTHFD2L and Its Implications for the Development of Isoform-Selective Inhibitors.,Scaletti ER, Gustafsson Westergren R, Andersson Y, Wiita E, Henriksson M, Homan EJ, Jemth AS, Helleday T, Stenmark P ChemMedChem. 2022 Sep 16;17(18):e202200274. doi: 10.1002/cmdc.202200274. Epub , 2022 Jul 6. PMID:35712863<ref>PMID:35712863</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 7qei" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Gustafsson R]] | |||
[[Category: Scaletti ER]] | |||
[[Category: Stenmark P]] | |||
Latest revision as of 16:17, 1 February 2024
Structure of human MTHFD2L in complex with TH7299Structure of human MTHFD2L in complex with TH7299
Structural highlights
FunctionMTD2L_HUMAN Bifunctional mitochondrial folate-interconverting enzyme that has both NAD/NADP-dependent methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities.[UniProtKB:D3ZUA0] Publication Abstract from PubMedMethylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial 1-carbon metabolism enzyme, which is an attractive anticancer drug target as it is highly upregulated in cancer but is not expressed in healthy adult cells. Selective MTHFD2 inhibitors could therefore offer reduced side-effects during treatment, which are common with antifolate drugs that target other 1C-metabolism enzymes. This task is challenging however, as MTHFD2 shares high sequence identity with the constitutively expressed isozymes cytosolic MTHFD1 and mitochondrial MTHFD2L. In fact, one of the most potent MTHFD2 inhibitors reported to date, TH7299, is actually more active against MTHFD1 and MTHFD2L. While structures of MTHFD2 and MTHFD1 exist, no MTHFD2L structures are available. We determined the first structure of MTHFD2L and its complex with TH7299, which reveals the structural basis for its highly potent MTHFD2L inhibition. Detailed analysis of the MTHFD2L structure presented here clearly highlights the challenges associated with developing truly isoform-selective MTHFD2 inhibitors. The First Structure of Human MTHFD2L and Its Implications for the Development of Isoform-Selective Inhibitors.,Scaletti ER, Gustafsson Westergren R, Andersson Y, Wiita E, Henriksson M, Homan EJ, Jemth AS, Helleday T, Stenmark P ChemMedChem. 2022 Sep 16;17(18):e202200274. doi: 10.1002/cmdc.202200274. Epub , 2022 Jul 6. PMID:35712863[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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