5TC4

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

Summary for 5TC4

• Entry DOI: 10.2210/pdb5tc4/pdb
• Descriptor: Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 4-(7-AMINO-9-HYDROXY-1-OXO-3,3A,4,5-TETRAHYDRO-2,5,6,8,9B-PENTAAZA-CYCLOPENTA[A]NAPHTHALEN-2-YL)-PHENYLCARBONYL-GLUTAMI C ACID, ... (5 entities in total)
• Functional Keywords: inhibitor, folate, cofactor, dehydrogenase, oxidoreductase
• Biological source: Homo sapiens (Human)
• Cellular location: Mitochondrion: P13995
• Total number of polymer chains: 1
• Total formula weight: 35544.57

Authors

Gustafsson, R.,Jemth, A.-S.,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. (deposition date: 2016-09-14, release date: 2016-12-14, Last modification date: 2024-01-17)

Primary citation

Gustafsson, R.,Jemth, A.S.,Gustafsson, N.M.,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.
Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor.
Cancer Res., 77:937-948, 2017

PubMed Abstract: 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. Because 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. .

PubMed: 27899380
DOI: 10.1158/0008-5472.CAN-16-1476

Experimental method

X-RAY DIFFRACTION (1.89 Å)