5k4l

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Crystal structure of KDM5A in complex with a naphthyridone inhibitor

Structural highlights

5k4l is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.179Å
Ligands:6QN, NI, ZN
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

Features from a high throughput screening (HTS) hit and a previously reported scaffold were combined to generate 1,7-naphthyridones as novel KDM5 enzyme inhibitors with nanomolar potencies. These molecules exhibited high selectivity over the related KDM4C and KDM2B isoforms. An X-ray co-crystal structure of a representative molecule bound to KDM5A showed that these inhibitors are competitive with the co-substrate (2-oxoglutarate or 2-OG).

Design and evaluation of 1,7-naphthyridones as novel KDM5 inhibitors.,Labadie SS, Dragovich PS, Cummings RT, Deshmukh G, Gustafson A, Han N, Harmange JC, Kiefer JR, Li Y, Liang J, Liederer BM, Liu Y, Manieri W, Mao W, Murray L, Ortwine DF, Trojer P, VanderPorten E, Vinogradova M, Wen L Bioorg Med Chem Lett. 2016 Sep 15;26(18):4492-6. doi: 10.1016/j.bmcl.2016.07.070., Epub 2016 Jul 29. PMID:27499454[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ Labadie SS, Dragovich PS, Cummings RT, Deshmukh G, Gustafson A, Han N, Harmange JC, Kiefer JR, Li Y, Liang J, Liederer BM, Liu Y, Manieri W, Mao W, Murray L, Ortwine DF, Trojer P, VanderPorten E, Vinogradova M, Wen L. Design and evaluation of 1,7-naphthyridones as novel KDM5 inhibitors. Bioorg Med Chem Lett. 2016 Sep 15;26(18):4492-6. doi: 10.1016/j.bmcl.2016.07.070., Epub 2016 Jul 29. PMID:27499454 doi:http://dx.doi.org/10.1016/j.bmcl.2016.07.070

Contents


PDB ID 5k4l

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