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PRMT5 is a promising drug target, playing a role in the pathomechanism of several diseases, especially in the progression of certain types of cancer. It was recently proved that the phosphorylation of PRMT5 on T80 residue increases its methyltransferase activity; furthermore, elevated levels of the enzyme were measured in the case of human hepatocellular carcinoma and other types of tumours. In this study, we constructed the complexes of the unmodified human PRMT5-methylosome protein 50 (MEP50) structure and its T80-phosphorylated variant in complex with the full-length histone H4 peptide. The full-length histone H4 was built in situ into the human PRMT5-MEP50 enzyme using experimental H4 fragments. Extensive molecular dynamic simulations and structure and energy analyses were performed for the complexed and apo protein partners, as well. Our results provided an atomic level explanation for two important experimental findings: (1) the increased methyltransferase activity of the phosphorylated PRMT5 when compared to the unmodified type; (2) the PRMT5 methylates only the free form of histone H4 not bound in the nucleosome. The atomic level complex structure H4-PRMT5-MEP50 will help the design of new inhibitors and in uncovering further structure\u2013function relationships of PRMT enzymes.<\/jats:p>","DOI":"10.3390\/ijms231911316","type":"journal-article","created":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T23:12:12Z","timestamp":1664320332000},"page":"11316","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Structural Effects of Phosphorylation of Protein Arginine Methyltransferase 5 on Its Binding to Histone H4"],"prefix":"10.3390","volume":"23","author":[{"given":"Rita","family":"B\u00f6rzsei","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Medical School, University of P\u00e9cs, 7624 P\u00e9cs, Hungary"},{"name":"J\u00e1nos Szent\u00e1gothai Research Centre & Centre for Neuroscience, University of P\u00e9cs, 7624 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bayartsetseg","family":"Bayarsaikhan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Medical School, University of P\u00e9cs, 7624 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bal\u00e1zs Zolt\u00e1n","family":"Zsid\u00f3","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Medical School, University of P\u00e9cs, 7624 P\u00e9cs, Hungary"},{"name":"J\u00e1nos Szent\u00e1gothai Research Centre & Centre for Neuroscience, University of P\u00e9cs, 7624 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2545-8275","authenticated-orcid":false,"given":"Be\u00e1ta","family":"Lontay","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8013-971X","authenticated-orcid":false,"given":"Csaba","family":"Het\u00e9nyi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Pharmacotherapy, Medical School, University of P\u00e9cs, 7624 P\u00e9cs, Hungary"},{"name":"J\u00e1nos Szent\u00e1gothai Research Centre & Centre for Neuroscience, University of P\u00e9cs, 7624 P\u00e9cs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/s41586-021-03520-4","article-title":"Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity","volume":"595","author":"Griffin","year":"2021","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/d41586-019-03122-1","article-title":"Histone lactylation links metabolism and gene regulation","volume":"574","author":"Izzo","year":"2019","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1038\/s41467-018-03895-5","article-title":"Functional crosstalk between histone H2B ubiquitylation and H2A modifications and variants","volume":"9","author":"Wojcik","year":"2018","journal-title":"Nat. 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