| Structural highlights
6boz is a 2 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: | KMT5A, PRSET7, SET07, SET8, SETD8 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[KMT5A_HUMAN] Protein-lysine N-methyltransferase that monomethylates both histones and non-histone proteins. Specifically monomethylates 'Lys-20' of histone H4 (H4K20me1). H4K20me1 is enriched during mitosis and represents a specific tag for epigenetic transcriptional repression. Mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes. Required for cell proliferation, probably by contributing to the maintenance of proper higher-order structure of DNA during mitosis. Involved in chromosome condensation and proper cytokinesis. Nucleosomes are preferred as substrate compared to free histones. Mediates monomethylation of p53/TP53 at 'Lys-382', leading to repress p53/TP53-target genes. Plays a negative role in TGF-beta response regulation and a positive role in cell migration.[1] [2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
Elucidating the conformational heterogeneity of proteins is essential for understanding protein function and developing exogenous ligands. With the rapid development of experimental and computational methods, it is of great interest to integrate these approaches to illuminate the conformational landscapes of target proteins. SETD8 is a protein lysine methyltransferase (PKMT), which functions in vivo via the methylation of histone and nonhistone targets. Utilizing covalent inhibitors and depleting native ligands to trap hidden conformational states, we obtained diverse X-ray structures of SETD8. These structures were used to seed distributed atomistic molecular dynamics simulations that generated a total of six milliseconds of trajectory data. Markov state models, built via an automated machine learning approach and corroborated experimentally, reveal how slow conformational motions and conformational states are relevant to catalysis. These findings provide molecular insight on enzymatic catalysis and allosteric mechanisms of a PKMT via its detailed conformational landscape.
The dynamic conformational landscape of the protein methyltransferase SETD8.,Chen S, Wiewiora RP, Meng F, Babault N, Ma A, Yu W, Qian K, Hu H, Zou H, Wang J, Fan S, Blum G, Pittella-Silva F, Beauchamp KA, Tempel W, Jiang H, Chen K, Skene RJ, Zheng YG, Brown PJ, Jin J, Luo C, Chodera JD, Luo M Elife. 2019 May 13;8. pii: 45403. doi: 10.7554/eLife.45403. PMID:31081496[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Nishioka K, Rice JC, Sarma K, Erdjument-Bromage H, Werner J, Wang Y, Chuikov S, Valenzuela P, Tempst P, Steward R, Lis JT, Allis CD, Reinberg D. PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin. Mol Cell. 2002 Jun;9(6):1201-13. PMID:12086618
- ↑ Fang J, Feng Q, Ketel CS, Wang H, Cao R, Xia L, Erdjument-Bromage H, Tempst P, Simon JA, Zhang Y. Purification and functional characterization of SET8, a nucleosomal histone H4-lysine 20-specific methyltransferase. Curr Biol. 2002 Jul 9;12(13):1086-99. PMID:12121615
- ↑ Julien E, Herr W. A switch in mitotic histone H4 lysine 20 methylation status is linked to M phase defects upon loss of HCF-1. Mol Cell. 2004 Jun 18;14(6):713-25. PMID:15200950 doi:http://dx.doi.org/10.1016/j.molcel.2004.06.008
- ↑ Xiao B, Jing C, Kelly G, Walker PA, Muskett FW, Frenkiel TA, Martin SR, Sarma K, Reinberg D, Gamblin SJ, Wilson JR. Specificity and mechanism of the histone methyltransferase Pr-Set7. Genes Dev. 2005 Jun 15;19(12):1444-54. Epub 2005 Jun 2. PMID:15933069 doi:http://dx.doi.org/10.1101/gad.1315905
- ↑ Couture JF, Collazo E, Brunzelle JS, Trievel RC. Structural and functional analysis of SET8, a histone H4 Lys-20 methyltransferase. Genes Dev. 2005 Jun 15;19(12):1455-65. Epub 2005 Jun 2. PMID:15933070 doi:10.1101/gad.1318405
- ↑ Sims JK, Houston SI, Magazinnik T, Rice JC. A trans-tail histone code defined by monomethylated H4 Lys-20 and H3 Lys-9 demarcates distinct regions of silent chromatin. J Biol Chem. 2006 May 5;281(18):12760-6. Epub 2006 Mar 3. PMID:16517599 doi:http://dx.doi.org/10.1074/jbc.M513462200
- ↑ Shi X, Kachirskaia I, Yamaguchi H, West LE, Wen H, Wang EW, Dutta S, Appella E, Gozani O. Modulation of p53 function by SET8-mediated methylation at lysine 382. Mol Cell. 2007 Aug 17;27(4):636-46. PMID:17707234 doi:http://dx.doi.org/10.1016/j.molcel.2007.07.012
- ↑ Abbas T, Mueller AC, Shibata E, Keaton M, Rossi M, Dutta A. CRL1-FBXO11 promotes Cdt2 ubiquitylation and degradation and regulates Pr-Set7/Set8-mediated cellular migration. Mol Cell. 2013 Mar 28;49(6):1147-58. doi: 10.1016/j.molcel.2013.02.003. Epub 2013, Mar 7. PMID:23478445 doi:http://dx.doi.org/10.1016/j.molcel.2013.02.003
- ↑ Chen S, Wiewiora RP, Meng F, Babault N, Ma A, Yu W, Qian K, Hu H, Zou H, Wang J, Fan S, Blum G, Pittella-Silva F, Beauchamp KA, Tempel W, Jiang H, Chen K, Skene RJ, Zheng YG, Brown PJ, Jin J, Luo C, Chodera JD, Luo M. The dynamic conformational landscape of the protein methyltransferase SETD8. Elife. 2019 May 13;8. pii: 45403. doi: 10.7554/eLife.45403. PMID:31081496 doi:http://dx.doi.org/10.7554/eLife.45403
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