4QKN

Crystal structure of FTO bound to a selective inhibitor

Summary for 4QKN

• Entry DOI: 10.2210/pdb4qkn/pdb
• Descriptor: Alpha-ketoglutarate-dependent dioxygenase FTO, N-OXALYLGLYCINE, 2-[(2,6-dichloro-3-methyl-phenyl)amino]benzoic acid, ... (6 entities in total)
• Functional Keywords: jellyroll folding, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus : Q9C0B1
• Total number of polymer chains: 1
• Total formula weight: 55297.94

Authors

Yang, C.-G.,Huang, Y.,Gan, J. (deposition date: 2014-06-07, release date: 2014-12-03, Last modification date: 2024-05-29)

Primary citation

Huang, Y.,Yan, J.,Li, Q.,Li, J.,Gong, S.,Zhou, H.,Gan, J.,Jiang, H.,Jia, G.F.,Luo, C.,Yang, C.G.
Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5.
Nucleic Acids Res., 43:373-384, 2015

PubMed Abstract: Two human demethylases, the fat mass and obesity-associated (FTO) enzyme and ALKBH5, oxidatively demethylate abundant N(6)-methyladenosine (m(6)A) residues in mRNA. Achieving a method for selective inhibition of FTO over ALKBH5 remains a challenge, however. Here, we have identified meclofenamic acid (MA) as a highly selective inhibitor of FTO. MA is a non-steroidal, anti-inflammatory drug that mechanistic studies indicate competes with FTO binding for the m(6)A-containing nucleic acid. The structure of FTO/MA has revealed much about the inhibitory function of FTO. Our newfound understanding, revealed herein, of the part of the nucleotide recognition lid (NRL) in FTO, for example, has helped elucidate the principles behind the selectivity of FTO over ALKBH5. Treatment of HeLa cells with the ethyl ester form of MA (MA2) has led to elevated levels of m(6)A modification in mRNA. Our collective results highlight the development of functional probes of the FTO enzyme that will (i) enable future biological studies and (ii) pave the way for the rational design of potent and specific inhibitors of FTO for use in medicine.

PubMed: 25452335
DOI: 10.1093/nar/gku1276

Experimental method

X-RAY DIFFRACTION (2.2 Å)