Insights into CARM1 methylation : design of selective inhibitors and peptide mimics : a structure based approach
type: Dataset
description: Protein aginine methyltransferases (PRMTs) have been implicated in a variety of biological processes. Coactivator-associated arginine methyltransferase 1 (CARM1 , also known as PRMT4) was identified as an enhancer of the transcriptional activation by several nuclear hormone receptors CARM1 is an enzyme which methylates the arginines of histones via a natural methyl donor, the SAdenosyh-Methionine (SAM). Recent studies have shown that CARM-1 is over-expressed in breastumors and in hormone dependent prostate tumors. The goal of this work is to understand at the molecular level the mode of binding of substrate/product arginine-containing peptides, reflectingstates prior and subsequent to methylation and the detailed mechanism of action of this protein. Several crystal structures of the catalytic domain of CARM1 have shown that cofactor-binding, such as S-Adenosyl-L -Homocysteine or sinefungin, produces large conformational changes in the catalytic domain. These crystal structures clearly illustrate that SAM binding is a prerequisite for peptide binding and build up the productive peptide binding site. Our strategy was to design fishhook molecules derivatives of the SAM capable of anchoring a mimic peptide of the histone H3 in order to test the co-crystallization in CARM1. Consequently, thanks to X-Ray structure, interactions involvement in the complexe CARM1/fishhook molecule/peptide could be determined. This strategy was do ne in three steps: the first one, described in the chapter 2, consisted in synthesizing SAManalogues with several modifications around sulfur atom. These compounds permitted to explore the "sulfonium pocket". The second step, described in chapter 3, consisted in synthesizing analogues of bisubstrats to explore "arginine binding pocket". Finally, the last step, described in the chapter 4 and 5, consisted in synthesizing SAM-peptide adducts to study "peptide binding domain". ln the chapter 4, the chosen method is the creation of covalent link between…
landing page: https://theses.hal.science/tel-00769956
identifier: NNT: 2012STRAF002
keyword: analogues-de-la-s-adenosyl-l-methionine
keyword: chimothechemical-sciencesother
keyword: coactivor-associated-arginine-methyltransferase-1
keyword: histone
keyword: infoeu-reposemanticsdoctoralthesis
keyword: modifications-epigenetiques
keyword: prmt4
keyword: protein-arginine-methyltransferases
keyword: proteines-arginines-methyltransferases
keyword: sam-analogues
keyword: sdvsalife-sciences-q-bioagricultural-sciences
keyword: theses
issued: 2026-05-15T14:12:43.817075
modified: 2026-05-15T14:12:43.817089
language: fr
contact point: Organization
  fn: CCSD

test_moissonnage_selune
type: Agent

Insights into CARM1 methylation : design of selective inhibitors and peptide mimics : a structure based approach
type: Distribution
format: HTML
access URL: https://theses.hal.science/tel-00769956
issued: 2026-05-15T14:12:43.824776
modified: 2026-05-15T14:12:43.771734