| Structural highlights
6bh4 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , |
| Gene: | KDM5A, JARID1A, RBBP2, RBP2 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[KDM5A_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 PubMed
Isomers of chiral drugs can exhibit marked differences in biological activities. We studied the binding and inhibitory activities of 12 compounds against KDM5A. Among them are two pairs of enantiomers representing two distinct inhibitor chemotypes, namely, ( R)- and ( S)-2-((2-chlorophenyl)(2-(piperidin-1-yl)ethoxy)methyl)-1 H-pyrrolo[3,2- b]pyridine-7-carboxylic acid (compounds N51 and N52) and ( R) - and ( S) -N-(1-(3-isopropyl-1 H-pyrazole-5-carbonyl)pyrrolidin-3-yl)cyclopropanecarboxamide (compounds N54 and N55). In vitro, the S enantiomer of the N51/N52 pair (N52) and the R enantiomer of the N54/N55 pair (N54) exhibited about 4- to 5-fold greater binding affinity. The more potent enzyme inhibition of KDM5A by the R-isoform for the cell-permeable N54/N55 pair translated to differences in growth inhibitory activity. We determined structures of the KDM5A catalytic domain in complex with all 12 inhibitors, which revealed the interactions (or lack thereof) responsible for the differences in binding affinity. These results provide insights to guide improvements in binding potency and avenues for development of cell permeable inhibitors of the KDM5 family.
Insights into the Action of Inhibitor Enantiomers against Histone Lysine Demethylase 5A.,Horton JR, Liu X, Wu L, Zhang K, Shanks J, Zhang X, Rai G, Mott BT, Jansen DJ, Kales SC, Henderson MJ, Pohida K, Fang Y, Hu X, Jadhav A, Maloney DJ, Hall MD, Simeonov A, Fu H, Vertino PM, Yan Q, Cheng X J Med Chem. 2018 Mar 23. doi: 10.1021/acs.jmedchem.8b00261. PMID:29537847[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Chan SW, Hong W. Retinoblastoma-binding protein 2 (Rbp2) potentiates nuclear hormone receptor-mediated transcription. J Biol Chem. 2001 Jul 27;276(30):28402-12. Epub 2001 May 17. PMID:11358960 doi:http://dx.doi.org/10.1074/jbc.M100313200
- ↑ Benevolenskaya EV, Murray HL, Branton P, Young RA, Kaelin WG Jr. Binding of pRB to the PHD protein RBP2 promotes cellular differentiation. Mol Cell. 2005 Jun 10;18(6):623-35. PMID:15949438 doi:http://dx.doi.org/10.1016/j.molcel.2005.05.012
- ↑ Iwase S, Lan F, Bayliss P, de la Torre-Ubieta L, Huarte M, Qi HH, Whetstine JR, Bonni A, Roberts TM, Shi Y. The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell. 2007 Mar 23;128(6):1077-88. Epub 2007 Feb 22. PMID:17320160 doi:10.1016/j.cell.2007.02.017
- ↑ Christensen J, Agger K, Cloos PA, Pasini D, Rose S, Sennels L, Rappsilber J, Hansen KH, Salcini AE, Helin K. RBP2 belongs to a family of demethylases, specific for tri-and dimethylated lysine 4 on histone 3. Cell. 2007 Mar 23;128(6):1063-76. Epub 2007 Feb 22. PMID:17320161 doi:S0092-8674(07)00182-1
- ↑ Klose RJ, Yan Q, Tothova Z, Yamane K, Erdjument-Bromage H, Tempst P, Gilliland DG, Zhang Y, Kaelin WG Jr. The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell. 2007 Mar 9;128(5):889-900. Epub 2007 Feb 22. PMID:17320163 doi:http://dx.doi.org/10.1016/j.cell.2007.02.013
- ↑ Horton JR, Liu X, Wu L, Zhang K, Shanks J, Zhang X, Rai G, Mott BT, Jansen DJ, Kales SC, Henderson MJ, Pohida K, Fang Y, Hu X, Jadhav A, Maloney DJ, Hall MD, Simeonov A, Fu H, Vertino PM, Yan Q, Cheng X. Insights into the Action of Inhibitor Enantiomers against Histone Lysine Demethylase 5A. J Med Chem. 2018 Mar 23. doi: 10.1021/acs.jmedchem.8b00261. PMID:29537847 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00261
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