Fig. 6
Comparison of the active site substrate binding modes for JMJD5 and related JmjC enzymes. Red/blue arrows indicate hydroxylation/demethylation sites, respectively. Active-site metals (Fe or Fe surrogates, Mn/Ni) are colour-coded spheres. Values represent distances (Å) from the metal to the oxidised carbon. a ycfDRM.Mn.NOG.L16(72–91) (PDB: 4CUG), b NO66.Mn.NOG.RPL8(205–224) (PDB: 4CCO), c PHF8.Fe.NOG.H3K4me3K9me2(2–25) (PDB: 3KV4), d KDM4A.Ni.NOG.H3K9me2(7–14) (PDB: 2OX0), e FIH.Fe.NOG.HIF-1α (786–826) (PDB: 1H2K), f JMJD5.Mn.NOG.RCCD1(139–142) (PDB: 6F4R). Note variations in the N- to C-substrate directionality in the active site cleft (indicated by black arrows), and variations in the hydroxylation site relative to the metal (boxed). JMJD5 binds substrates (f) with the same substrate N/C-directionality, as for most KDMs (KDM4A, KDM6B and KDM6A, d), but differing from that for RIOX (a, b) and for one KDM, PHF8 (and likely other KDM2/7 subfamily members, c). Overall, the mode of JMJD5-catalysed hydroxylation more closely resembles that of FIH (e) compared to other JmjC-hydroxylases and KDMs, consistent with the proposal that the FIH/JMJD5 subgroup of JmjC-hydroxylases evolved from prokaryotic RIOX including by loss of the 'Winged helix' (WH) domains, which are located at the C-terminus of all RIOX30,32
