5O22

E. coli FolD in complex with carolacton

Summary for 5O22

• Entry DOI: 10.2210/pdb5o22/pdb
• Descriptor: Bifunctional protein FolD, Carolacton, ... (6 entities in total)
• Functional Keywords: carolacton, fold, natural product, inhibitor, oxidoreductase
• Biological source: Escherichia coli (strain K12); More
• Total number of polymer chains: 4
• Total formula weight: 126579.48

Authors

Koehnke, J.,Sikandar, A. (deposition date: 2017-05-19, release date: 2018-02-28, Last modification date: 2024-01-17)

Primary citation

Fu, C.,Sikandar, A.,Donner, J.,Zaburannyi, N.,Herrmann, J.,Reck, M.,Wagner-Dobler, I.,Koehnke, J.,Muller, R.
The natural product carolacton inhibits folate-dependent C1 metabolism by targeting FolD/MTHFD.
Nat Commun, 8:1529-1529, 2017

PubMed Abstract: The natural product carolacton is a macrolide keto-carboxylic acid produced by the myxobacterium Sorangium cellulosum, and was originally described as an antibacterial compound. Here we show that carolacton targets FolD, a key enzyme from the folate-dependent C1 metabolism. We characterize the interaction between bacterial FolD and carolacton biophysically, structurally and biochemically. Carolacton binds FolD with nanomolar affinity, and the crystal structure of the FolD-carolacton complex reveals the mode of binding. We show that the human FolD orthologs, MTHFD1 and MTHFD2, are also inhibited in the low nM range, and that micromolar concentrations of carolacton inhibit the growth of cancer cell lines. As mitochondrial MTHFD2 is known to be upregulated in cancer cells, it may be possible to use carolacton as an inhibitor tool compound to assess MTHFD2 as an anti-cancer target.

PubMed: 29142318
DOI: 10.1038/s41467-017-01671-5

Experimental method

X-RAY DIFFRACTION (2.1 Å)