PDBsum entry 4cxx

Oxidoreductase

PDB id: 4cxx

Contents

Protein chain

434 a.a.

Ligands

640

Metals

_NI

Waters ×113

PDB id:

4cxx

Name:

Oxidoreductase

Title:

Crystal structure of human fto in complex with acylhydrazine inhibitor 16

Structure:

Alpha-ketoglutarate-dependent dioxygenase fto. Chain: a. Fragment: demethylase, residues 32-505. Synonym: fat mass and obesity-associated protein. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 511693.

Resolution:

2.76Å R-factor: 0.213 R-free: 0.263

Authors:

D.W.Toh,L.Sun,J.Tan,Y.Chen,L.Z.M.Lau,W.Hong,E.C.Y.Woon,Y.G.Gao

Key ref:

J.D.W.Toh et al. (2015). A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor of N⁶-methyladenosine demethylase FTO. Chem Sci, 6, 112-122. PubMed id: 28553460

Date:

09-Apr-14 Release date: 01-Oct-14

Protein chain

Q9C0B1  (FTO_HUMAN) -  Alpha-ketoglutarate-dependent dioxygenase FTO from Homo sapiens

Seq: 505 a.a.

Struc: 434 a.a.*

* PDB and UniProt seqs differ at 5 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: E.C.1.14.11.- - ?????
• Enzyme class 2: E.C.1.14.11.53 - mRNA N(6)-methyladenine demethylase.
• Reaction: an N₆-methyladenosine in mRNA + 2-oxoglutarate + O2 = an adenosine in mRNA + formaldehyde + succinate + CO2
• Cofactor: Fe(3+)

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

Chem Sci 6:112-122 (2015)

PubMed id: 28553460

A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor of N⁶-methyladenosine demethylase FTO.

J.D.W.Toh, L.Sun, L.Z.M.Lau, J.Tan, J.J.A.Low, C.W.Q.Tang, E.J.Y.Cheong, M.J.H.Tan, Y.Chen, W.Hong, Y.G.Gao, E.C.Y.Woon.

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 12. The distinct selectivity of 12 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.