4NJ4: Crystal Structure Of Human Alkbh5

ALKBH5 is a 2-oxoglutarate (2OG) and ferrous iron-dependent nucleic acid oxygenase (NAOX) that catalyzes the demethylation of N(6)-methyladenine in RNA. ALKBH5 is upregulated under hypoxia and plays a role in spermatogenesis. We describe a crystal structure of human ALKBH5 (residues 66-292) to 2.0 A resolution. ALKBH566-292 has a double-stranded beta-helix core fold as observed in other 2OG and iron-dependent oxygenase family members. The active site metal is octahedrally coordinated by an HXD...H motif (comprising residues His204, Asp206 and His266) and three water molecules. ALKBH5 shares a nucleotide recognition lid and conserved active site residues with other NAOXs. A large loop (betaIV-V) in ALKBH5 occupies a similar region as the L1 loop of the fat mass and obesity-associated protein that is proposed to confer single-stranded RNA selectivity. Unexpectedly, a small molecule inhibitor, IOX3, was observed covalently attached to the side chain of Cys200 located outside of the active site. Modelling substrate into the active site based on other NAOX-nucleic acid complexes reveals conserved residues important for recognition and demethylation mechanisms. The structural insights will aid in the development of inhibitors selective for NAOXs, for use as functional probes and for therapeutic benefit.
PDB ID: 4NJ4Download
MMDB ID: 116700
PDB Deposition Date: 2013/11/8
Updated in MMDB: 2014/05
Experimental Method:
x-ray diffraction
Resolution: 2.02  Å
Source Organism:
Similar Structures:
Biological Unit for 4NJ4: monomeric; determined by author and by software (PISA)
Molecular Components in 4NJ4
Label Count Molecule
Protein (1 molecule)
RNA Demethylase Alkbh5(Gene symbol: ALKBH5)
Molecule annotation
Chemicals (7 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB