4CXW

Crystal structure of human FTO in complex with subfamily-selective inhibitor 12

Summary for 4CXW

• Entry DOI: 10.2210/pdb4cxw/pdb
• Related: 4CXX 4CXY 4CXZ 4CY0
• Descriptor: ALPHA-KETOGLUTARATE-DEPENDENT DIOXYGENASE FTO, NICKEL (II) ION, (2E)-4-[N'-(4-benzyl-pyridine-3-carbonyl)-hydrazino]-4-oxo-but-2-enoic acid, ... (4 entities in total)
• Functional Keywords: oxidoreductase, small molecular probe
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Nucleus : Q9C0B1
• Total number of polymer chains: 1
• Total formula weight: 57207.06

Authors

Toh, D.W.,Sun, L.,Tan, J.,Chen, Y.,Lau, L.Z.M.,Hong, W.,Woon, E.C.Y.,Gao, Y.G. (deposition date: 2014-04-09, release date: 2014-10-01, Last modification date: 2023-12-20)

Primary citation

Toh, J.D.W.,Sun, L.,Lau, L.Z.M.,Tan, J.,Low, J.J.A.,Tang, C.W.Q.,Cheong, E.J.Y.,Tan, M.J.H.,Chen, Y.,Hong, W.,Gao, Y.G.,Woon, E.C.Y.
A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor ofN6-methyladenosine demethylase FTO.
Chem Sci, 6:112-122, 2015

PubMed Abstract: The AlkB family of nucleic acid demethylases are of intense biological and medical interest because of their roles in nucleic acid repair and epigenetic modification. However their functional and molecular mechanisms are unclear, hence, there is strong interest in developing selective inhibitors for them. Here we report the identification of key residues within the nucleotide-binding sites of the AlkB subfamilies that likely determine their substrate specificity. We further provide proof of principle that a strategy exploiting these inherent structural differences can enable selective and potent inhibition of the AlkB subfamilies. This is demonstrated by the first report of a subfamily-selective and cell-active FTO inhibitor . The distinct selectivity of for FTO against other AlkB subfamilies and 2OG oxygenases shall be of considerable interest with regards to its potential use as a functional probe. The strategy outlined here is likely applicable to other AlkB subfamilies, and, more widely, to other 2OG oxygenases.

PubMed: 28553460
DOI: 10.1039/c4sc02554g

Experimental method

X-RAY DIFFRACTION (3.1 Å)