5e6h | pdb_00005e6h
A Linked Jumonji Domain of the KDM5A Lysine Demethylase
Structural highlights
FunctionKDM5A_HUMAN Histone demethylase that specifically demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-9', H3 'Lys-27', H3 'Lys-36', H3 'Lys-79' or H4 'Lys-20'. Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-4'. May stimulate transcription mediated by nuclear receptors. May be involved in transcriptional regulation of Hox proteins during cell differentiation. May participate in transcriptional repression of cytokines such as CXCL12. Plays a role in the regulation of the circadian rhythm and in maintaining the normal periodicity of the circadian clock. In a histone demethylase-independent manner, acts as a coactivator of the CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER1/2 and other clock-controlled genes and increases histone acetylation at PER1/2 promoters by inhibiting the activity of HDAC1 (By similarity).[UniProtKB:Q3UXZ9][1] [2] [3] [4] [5] Publication Abstract from PubMedThe KDM5/JARID1 family of Fe(II)- and alpha-ketoglutarate-dependent demethylases remove methyl groups from tri- and di-methylated lysine 4 of histone H3. Accumulating evidence from primary tumors and model systems support a role for KDM5A (JARID1A/RBP2) and KDM5B (JARID1B/PLU1) as oncogenic drivers. The KDM5 family is unique among the Jumonji domain-containing histone demethylases in that there is an atypical insertion of a DNA-binding ARID domain and a histone-binding PHD domain into the Jumonji domain, which separates the catalytic domain into two fragments (JmjN and JmjC). Here we demonstrate that internal deletion of the ARID and PHD1 domains has a negligible effect on in vitro enzymatic kinetics of the KDM5 family of enzymes. We present a crystal structure of the linked JmjN-JmjC domain from KDM5A, which reveals that the linked domain fully reconstitutes the cofactor (metal ion and alpha-ketoglutarate) binding characteristics of other structurally-characterized Jumonji domain demethylases. Docking studies with GSK-J1, a selective inhibitor of the KDM6/KDM5 sub-families, identify critical residues for binding of the inhibitor to the reconstituted KDM5 Jumonji domain. Further, we found that GSK-J1 inhibited the demethylase activity of KDM5C with 8.5-fold increased potency compared to that of KDM5B at 1 mM alpha-ketoglutarate. In contrast, JIB-04 (a pan-inhibitor of the Jumonji demethylase superfamily) had the opposite effect and was approximately 8-fold more potent against KDM5B than KDM5C. Interestingly, the relative selectivity of JIB-04 towards KDM5B over KDM5C in vitro translates to a ~10-50-fold greater growth inhibitory activity against breast cancer cell lines. These data define the minimal requirements for enzymatic activity of the KDM5 family to be the linked JmjN-JmjC domain coupled with the immediate C- terminal helical Zn-binding domain and provide structural characterization of the linked JmjN-JmjC domain for the KDM5 family, which should prove useful in the design of KDM5 demethylase inhibitors with improved potency and selectivity. Characterization of a linked Jumonji domain of the KDM5/JARID1 family of histone H3 lysine 4 demethylases.,Horton JR, Engstrom A, Zoeller EL, Liu X, Shanks JR, Zhang X, Johns MA, Vertino PM, Fu H, Cheng X J Biol Chem. 2015 Dec 8. pii: jbc.M115.698449. PMID:26645689[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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