6S4A

Structure of human MTHFD2 in complex with TH9028

Summary for 6S4A

• Entry DOI: 10.2210/pdb6s4a/pdb
• Descriptor: Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial, (2~{S})-2-[[5-[[2,4-bis(azanyl)-6-oxidanylidene-5~{H}-pyrimidin-5-yl]carbamoylamino]pyridin-2-yl]carbonylamino]-4-(1~{H}-1,2,3,4-tetrazol-5-yl)butanoic acid, PHOSPHATE ION, ... (6 entities in total)
• Functional Keywords: oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 72270.17

Authors

Gustafsson, R.,Scaletti, E.R.,Bonagas, N.,Gustafsson, N.M.,Henriksson, M.,Abdurakhmanov, E.,Andersson, Y.,Bengtsson, C.,Borhade, S.,Desroses, M.,Farnegardh, K.,Garg, N.,Gokturk, C.,Haraldsson, M.,Iliev, P.,Jarvius, M.,Jemth, A.S.,Kalderen, C.,Karsten, S.,Klingegard, F.,Koolmeister, T.,Martens, U.,Llona-Minguez, S.,Loseva, O.,Marttila, P.,Michel, M.,Moulson, R.,Nordstrom, H.,Paulin, C.,Pham, T.,Pudelko, L.,Rasti, A.,Roos, A.K.,Sarno, A.,Sandberg, L.,Scobie, M.,Sjoberg, B.,Svensson, R.,Unterlass, J.E.,Vallin, K.,Vo, D.,Wiita, E.,Warpman-Berglund, U.,Homan, E.J.,Helleday, T.,Stenmark, P. (deposition date: 2019-06-27, release date: 2021-07-07, Last modification date: 2024-06-19)

Primary citation

Bonagas, N.,Gustafsson, N.M.S.,Henriksson, M.,Marttila, P.,Gustafsson, R.,Wiita, E.,Borhade, S.,Green, A.C.,Vallin, K.S.A.,Sarno, A.,Svensson, R.,Gokturk, C.,Pham, T.,Jemth, A.S.,Loseva, O.,Cookson, V.,Kiweler, N.,Sandberg, L.,Rasti, A.,Unterlass, J.E.,Haraldsson, M.,Andersson, Y.,Scaletti, E.R.,Bengtsson, C.,Paulin, C.B.J.,Sanjiv, K.,Abdurakhmanov, E.,Pudelko, L.,Kunz, B.,Desroses, M.,Iliev, P.,Farnegardh, K.,Kramer, A.,Garg, N.,Michel, M.,Haggblad, S.,Jarvius, M.,Kalderen, C.,Jensen, A.B.,Almlof, I.,Karsten, S.,Zhang, S.M.,Haggblad, M.,Eriksson, A.,Liu, J.,Glinghammar, B.,Nekhotiaeva, N.,Klingegard, F.,Koolmeister, T.,Martens, U.,Llona-Minguez, S.,Moulson, R.,Nordstrom, H.,Parrow, V.,Dahllund, L.,Sjoberg, B.,Vargas, I.L.,Vo, D.D.,Wannberg, J.,Knapp, S.,Krokan, H.E.,Arvidsson, P.I.,Scobie, M.,Meiser, J.,Stenmark, P.,Berglund, U.W.,Homan, E.J.,Helleday, T.
Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress.
Nat Cancer, 3:156-172, 2022

PubMed Abstract: The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors.

PubMed: 35228749
DOI: 10.1038/s43018-022-00331-y

Experimental method

X-RAY DIFFRACTION (1.95 Å)