View source for 9isr


==Human MTHFD1 in complex with compound 16g==
<StructureSection load='9isr' size='340' side='right'caption='[[9isr]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9isr]] 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=9ISR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9ISR 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]] 2.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1L24:(2~{S})-2-[[4-[[2,4-bis(azanyl)-6-oxidanylidene-1~{H}-pyrimidin-5-yl]carbamoylamino]-3-chloranyl-phenyl]carbonylamino]-4-(1~{H}-1,2,3,4-tetrazol-5-yl)butanoic+acid'>A1L24</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</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=9isr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9isr OCA], [https://pdbe.org/9isr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9isr RCSB], [https://www.ebi.ac.uk/pdbsum/9isr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9isr ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/C1TC_HUMAN C1TC_HUMAN] Defects in MTHFD1 may be a cause of susceptibility to folate-sensitive neural tube defects (FS-NTD) [MIM:[https://omim.org/entry/601634 601634]. The most common NTDs are open spina bifida (myelomeningocele) and anencephaly. Genetic defects in MTHFD1 may affect the risk of spina bifida via the maternal rather than the embryonic genotype.<ref>PMID:9611072</ref> <ref>PMID:12384833</ref> <ref>PMID:16552426</ref>   Genetic variation in MTHFD1 could be associated with susceptibility to colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500].
== Function ==
[https://www.uniprot.org/uniprot/C1TC_HUMAN C1TC_HUMAN] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2 (MTHFD2), a pivotal mitochondrial enzyme in one-carbon metabolism, is significantly upregulated in various cancers but minimally expressed in normal proliferating cells. In contrast, MTHFD1, which performs similar functions, is predominantly expressed in normal cells. Therefore, targeting MTHFD2 with selective inhibitors holds promise for a broader therapeutic window with reduced toxicity and fewer side effects. This study identified selective 2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl ureido-based derivatives through systematic chemical modifications and SAR studies. Structural biology investigations revealed substitutions in the phenyl ring and tail region modulate potency and selectivity toward MTHFD2. Additionally, a comprehensive cell screening platform revealed acute myeloid leukemia cells with FLT3 internal tandem duplication mutations are particularly sensitive to these inhibitors. Furthermore, synergistic effects were observed when combining potential compounds with Alimta. Compound 16e emerged as a leading candidate, demonstrating superior inhibition and selectivity for MTHFD2, favorable pharmacokinetics, and potent antitumor efficacy in MOLM-14 xenograft models.

Development of Potent and Selective Inhibitors of Methylenetetrahydrofolate Dehydrogenase 2 for Targeting Acute Myeloid Leukemia: SAR, Structural Insights, and Biological Characterization.,Chang HH, Lee LC, Hsu T, Peng YH, Huang CH, Yeh TK, Lu CT, Huang ZT, Hsueh CC, Kung FC, Lin LM, Huang YC, Wang YH, Li LH, Tang YC, Chang L, Hsieh CC, Jiaang WT, Kuo CC, Wu SY J Med Chem. 2024 Dec 12;67(23):21106-21125. doi: 10.1021/acs.jmedchem.4c01775. , Epub 2024 Nov 26. PMID:39591507<ref>PMID:39591507</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9isr" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Lee LC]]
[[Category: Wu SY]]