6dq9

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Linked KDM5A JMJ Domain Bound to the Covalent Inhibitor N69 i.e. [2-((3-acrylamidophenyl)(2-(piperidin-1-yl)ethoxy)methyl)thieno[3,2-b]pyridine-7-carboxylic acid]

Structural highlights

6dq9 is a 1 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 1.748Å
Ligands:DMS, EDO, GOL, H74, MN
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

The active sites of hundreds of human alpha-ketoglutarate (alphaKG) and Fe(II)-dependent dioxygenases are exceedingly well preserved, which challenges the design of selective inhibitors. We identified a noncatalytic cysteine (Cys481 in KDM5A) near the active sites of KDM5 histone H3 lysine 4 demethylases, which is absent in other histone demethylase families, that could be explored for interaction with the cysteine-reactive electrophile acrylamide. We synthesized analogs of a thienopyridine-based inhibitor chemotype, namely, 2-((3-aminophenyl)(2-(piperidin-1-yl)ethoxy)methyl)thieno[3,2- b]pyridine-7-carboxylic acid (N70) and a derivative containing a (dimethylamino)but-2-enamido)phenyl moiety (N71) designed to form a covalent interaction with Cys481. We characterized the inhibitory and binding activities against KDM5A and determined the cocrystal structures of the catalytic domain of KDM5A in complex with N70 and N71. Whereas the noncovalent inhibitor N70 displayed alphaKG-competitive inhibition that could be reversed after dialysis, inhibition by N71 was dependent on enzyme concentration and persisted even after dialysis, consistent with covalent modification.

Structure-Based Engineering of Irreversible Inhibitors against Histone Lysine Demethylase KDM5A.,Horton JR, Woodcock CB, Chen Q, Liu X, Zhang X, Shanks J, Rai G, Mott BT, Jansen DJ, Kales SC, Henderson MJ, Cyr M, Pohida K, Hu X, Shah P, Xu X, Jadhav A, Maloney DJ, Hall MD, Simeonov A, Fu H, Vertino PM, Cheng X J Med Chem. 2018 Dec 13;61(23):10588-10601. doi: 10.1021/acs.jmedchem.8b01219., Epub 2018 Nov 15. PMID:30392349[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. ↑ Horton JR, Woodcock CB, Chen Q, Liu X, Zhang X, Shanks J, Rai G, Mott BT, Jansen DJ, Kales SC, Henderson MJ, Cyr M, Pohida K, Hu X, Shah P, Xu X, Jadhav A, Maloney DJ, Hall MD, Simeonov A, Fu H, Vertino PM, Cheng X. Structure-Based Engineering of Irreversible Inhibitors against Histone Lysine Demethylase KDM5A. J Med Chem. 2018 Dec 13;61(23):10588-10601. doi: 10.1021/acs.jmedchem.8b01219., Epub 2018 Nov 15. PMID:30392349 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b01219

Contents


PDB ID 6dq9

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