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==Crystal structure of human mitochondrial methylenetetrahydrofolate dehydrogenase-cyclohydrolase (MTHFD2) in complex with LY345899 and cofactors==
==Crystal structure of human mitochondrial methylenetetrahydrofolate dehydrogenase-cyclohydrolase (MTHFD2) in complex with LY345899 and cofactors==
<StructureSection load='5tc4' size='340' side='right' caption='[[5tc4]], [[Resolution|resolution]] 1.89&Aring;' scene=''>
<StructureSection load='5tc4' size='340' side='right'caption='[[5tc4]], [[Resolution|resolution]] 1.89&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5tc4]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TC4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TC4 FirstGlance]. <br>
<table><tr><td colspan='2'>[[5tc4]] 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=5TC4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TC4 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=L34:4-(7-AMINO-9-HYDROXY-1-OXO-3,3A,4,5-TETRAHYDRO-2,5,6,8,9B-PENTAAZA-CYCLOPENTA[A]NAPHTHALEN-2-YL)-PHENYLCARBONYL-GLUTAMIC+ACID'>L34</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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]] 1.89&#8491;</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=5tc4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tc4 OCA], [http://pdbe.org/5tc4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tc4 RCSB], [http://www.ebi.ac.uk/pdbsum/5tc4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tc4 ProSAT]</span></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=L34:4-(7-AMINO-9-HYDROXY-1-OXO-3,3A,4,5-TETRAHYDRO-2,5,6,8,9B-PENTAAZA-CYCLOPENTA[A]NAPHTHALEN-2-YL)-PHENYLCARBONYL-GLUTAMIC+ACID'>L34</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=5tc4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tc4 OCA], [https://pdbe.org/5tc4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tc4 RCSB], [https://www.ebi.ac.uk/pdbsum/5tc4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tc4 ProSAT]</span></td></tr>
</table>
</table>
<div style="background-color:#fffaf0;">
== Function ==
== Publication Abstract from PubMed ==
[https://www.uniprot.org/uniprot/MTDC_HUMAN MTDC_HUMAN]
To sustain their proliferation, cancer cells become dependent on one-carbon metabolism to support purine and thymidylate synthesis. Indeed, one of the most highly upregulated enzymes during neoplastic transformation is MTHFD2, a mitochondrial methylenetetrahydrofolate dehydrogenase and cyclohydrolase involved in one-carbon metabolism. Since MTHFD2 is expressed normally only during embryonic development, it offers a disease-selective therapeutic target for eradicating cancer cells while sparing healthy cells. Here we report the synthesis and preclinical characterization of the first inhibitor of human MTHFD2. We also disclose the first crystal structure of MTHFD2 in complex with a substrate-based inhibitor and the enzyme cofactors NAD+ and inorganic phosphate. Our work provides a rationale for continued development of a structural framework for the generation of potent and selective MTHFD2 inhibitors for cancer treatment.


Crystal structure of the emerging cancer target MTHFD2 in complex with a substrate-based inhibitor.,Gustafsson R, Jemth AS, Gustafsson Sheppard N, Farnegardh K, Loseva O, Wiita E, Bonagas N, Dahllund L, Llona-Minguez S, Haggblad M, Henriksson M, Andersson Y, Homan E, Helleday T, Stenmark P Cancer Res. 2016 Nov 29. pii: canres.1476.2016. PMID:27899380<ref>PMID:27899380</ref>
==See Also==
 
*[[Cyclohydrolase 3D structures|Cyclohydrolase 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5tc4" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Andersson, Y]]
[[Category: Homo sapiens]]
[[Category: Bonagas, N]]
[[Category: Large Structures]]
[[Category: Dahllund, L]]
[[Category: Andersson Y]]
[[Category: Farnegardh, K]]
[[Category: Bonagas N]]
[[Category: Gustafsson, R]]
[[Category: Dahllund L]]
[[Category: Haggblad, M]]
[[Category: Farnegardh K]]
[[Category: Helleday, T]]
[[Category: Gustafsson R]]
[[Category: Henriksson, M]]
[[Category: Gustafsson Sheppard N]]
[[Category: Homan, E]]
[[Category: Haggblad M]]
[[Category: Jemth, A S]]
[[Category: Helleday T]]
[[Category: Llona-Minguez, S]]
[[Category: Henriksson M]]
[[Category: Loseva, O]]
[[Category: Homan E]]
[[Category: Sheppard, N Gustafsson]]
[[Category: Jemth A-S]]
[[Category: Stenmark, P]]
[[Category: Llona-Minguez S]]
[[Category: Wiita, E]]
[[Category: Loseva O]]
[[Category: Cofactor]]
[[Category: Stenmark P]]
[[Category: Dehydrogenase]]
[[Category: Wiita E]]
[[Category: Folate]]
[[Category: Inhibitor]]
[[Category: Oxidoreductase]]

Latest revision as of 18:39, 6 March 2024

Crystal structure of human mitochondrial methylenetetrahydrofolate dehydrogenase-cyclohydrolase (MTHFD2) in complex with LY345899 and cofactorsCrystal structure of human mitochondrial methylenetetrahydrofolate dehydrogenase-cyclohydrolase (MTHFD2) in complex with LY345899 and cofactors

Structural highlights

5tc4 is a 1 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 1.89Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MTDC_HUMAN

See Also

5tc4, resolution 1.89Å

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