7faj

From Proteopedia

(Difference between revisions)

Revision as of 10:59, 16 February 2022

CARM1 bound with compound 43

Structural highlights

7faj is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Activity:	Type I protein arginine methyltransferase, with EC number 2.1.1.319
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[CARM1_HUMAN] Methylates (mono- and asymmetric dimethylation) the guanidino nitrogens of arginyl residues in several proteins involved in DNA packaging, transcription regulation, pre-mRNA splicing, and mRNA stability. Recruited to promoters upon gene activation together with histone acetyltransferases from EP300/P300 and p160 families, methylates histone H3 at 'Arg-17' (H3R17me), forming mainly asymmetric dimethylarginine (H3R17me2a), leading to activate transcription via chromatin remodeling. During nuclear hormone receptor activation and TCF7L2/TCF4 activation, acts synergically with EP300/P300 and either one of the p160 histone acetyltransferases NCOA1/SRC1, NCOA2/GRIP1 and NCOA3/ACTR or CTNNB1/beta-catenin to activate transcription. During myogenic transcriptional activation, acts together with NCOA3/ACTR as a coactivator for MEF2C. During monocyte inflammatory stimulation, acts together with EP300/P300 as a coactivator for NF-kappa-B. Acts as coactivator for PPARG, promotes adipocyte differentiation and the accumulation of brown fat tissue. Plays a role in the regulation of pre-mRNA alternative splicing by methylation of splicing factors. Also seems to be involved in p53/TP53 transcriptional activation. Methylates EP300/P300, both at 'Arg-2142', which may loosen its interaction with NCOA2/GRIP1, and at 'Arg-580' and 'Arg-604' in the KIX domain, which impairs its interaction with CREB and inhibits CREB-dependent transcriptional activation. Also methylates arginine residues in RNA-binding proteins PABPC1, ELAVL1 and ELAV4, which may affect their mRNA-stabilizing properties and the half-life of their target mRNAs.^[1] ^[2]

Publication Abstract from PubMed

CARM1 is a protein arginine methyltransferase and acts as a transcriptional coactivator regulating multiple biological processes. Aberrant expression of CARM1 has been related to the progression of multiple types of cancers, and therefore CARM1 was considered as a promising drug target. In the present work, we report the structure-based discovery of a series of N(1)-(3-(pyrimidin-2-yl)benzyl)ethane-1,2-diamines as potent CARM1 inhibitors, in which compound 43 displays high potency and selectivity. With the advantage of excellent tissue distribution, compound 43 demonstrated good in vivo efficacy for solid tumors. Furthermore, from the detailed immuno-oncology study with MC38 C57BL/6J xenograft model, we confirmed that this chemical probe 43 has profound effects in tumor immunity, which paves the way for future studies on the modulation of arginine post-translational modification that could be utilized in solid tumor treatment and cancer immunotherapy.

Structure-Based Discovery of Potent CARM1 Inhibitors for Solid Tumor and Cancer Immunology Therapy.,Zhang Z, Guo Z, Xu X, Cao D, Yang H, Li Y, Shi Q, Du Z, Guo X, Wang X, Chen D, Zhang Y, Chen L, Zhou K, Li J, Geng M, Huang X, Xiong B J Med Chem. 2021 Nov 15. doi: 10.1021/acs.jmedchem.1c01308. PMID:34781683^[3]

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

References

↑ Miao F, Li S, Chavez V, Lanting L, Natarajan R. Coactivator-associated arginine methyltransferase-1 enhances nuclear factor-kappaB-mediated gene transcription through methylation of histone H3 at arginine 17. Mol Endocrinol. 2006 Jul;20(7):1562-73. Epub 2006 Feb 23. PMID:16497732 doi:me.2005-0365
↑ Lakowski TM, Frankel A. Kinetic analysis of human protein arginine N-methyltransferase 2: formation of monomethyl- and asymmetric dimethyl-arginine residues on histone H4. Biochem J. 2009 Jun 26;421(2):253-61. doi: 10.1042/BJ20090268. PMID:19405910 doi:10.1042/BJ20090268
↑ Zhang Z, Guo Z, Xu X, Cao D, Yang H, Li Y, Shi Q, Du Z, Guo X, Wang X, Chen D, Zhang Y, Chen L, Zhou K, Li J, Geng M, Huang X, Xiong B. Structure-Based Discovery of Potent CARM1 Inhibitors for Solid Tumor and Cancer Immunology Therapy. J Med Chem. 2021 Nov 15. doi: 10.1021/acs.jmedchem.1c01308. PMID:34781683 doi:http://dx.doi.org/10.1021/acs.jmedchem.1c01308

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7faj"

@@ Line 1: / Line 1: @@
 ==CARM1 bound with compound 43==
-<StructureSection load='7faj' size='340' side='right'caption='[[7faj]]' scene=''>
+<StructureSection load='7faj' size='340' side='right'caption='[[7faj]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7FAJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7FAJ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7faj]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7FAJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7FAJ FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7faj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7faj OCA], [https://pdbe.org/7faj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7faj RCSB], [https://www.ebi.ac.uk/pdbsum/7faj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7faj ProSAT]</span></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=XJ4:N-[[3-[4-(3,5-dimethyl-1,2-oxazol-4-yl)-5-methyl-6-phenylazanyl-pyrimidin-2-yl]phenyl]methyl]-N-methyl-ethane-1,2-diamine'>XJ4</scene></td></tr>
+<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Type_I_protein_arginine_methyltransferase Type I protein arginine methyltransferase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.319 2.1.1.319] </span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7faj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7faj OCA], [https://pdbe.org/7faj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7faj RCSB], [https://www.ebi.ac.uk/pdbsum/7faj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7faj ProSAT]</span></td></tr>
 </table>
+== Function ==
+[[https://www.uniprot.org/uniprot/CARM1_HUMAN CARM1_HUMAN]] Methylates (mono- and asymmetric dimethylation) the guanidino nitrogens of arginyl residues in several proteins involved in DNA packaging, transcription regulation, pre-mRNA splicing, and mRNA stability. Recruited to promoters upon gene activation together with histone acetyltransferases from EP300/P300 and p160 families, methylates histone H3 at 'Arg-17' (H3R17me), forming mainly asymmetric dimethylarginine (H3R17me2a), leading to activate transcription via chromatin remodeling. During nuclear hormone receptor activation and TCF7L2/TCF4 activation, acts synergically with EP300/P300 and either one of the p160 histone acetyltransferases NCOA1/SRC1, NCOA2/GRIP1 and NCOA3/ACTR or CTNNB1/beta-catenin to activate transcription. During myogenic transcriptional activation, acts together with NCOA3/ACTR as a coactivator for MEF2C. During monocyte inflammatory stimulation, acts together with EP300/P300 as a coactivator for NF-kappa-B. Acts as coactivator for PPARG, promotes adipocyte differentiation and the accumulation of brown fat tissue. Plays a role in the regulation of pre-mRNA alternative splicing by methylation of splicing factors. Also seems to be involved in p53/TP53 transcriptional activation. Methylates EP300/P300, both at 'Arg-2142', which may loosen its interaction with NCOA2/GRIP1, and at 'Arg-580' and 'Arg-604' in the KIX domain, which impairs its interaction with CREB and inhibits CREB-dependent transcriptional activation. Also methylates arginine residues in RNA-binding proteins PABPC1, ELAVL1 and ELAV4, which may affect their mRNA-stabilizing properties and the half-life of their target mRNAs.<ref>PMID:16497732</ref> <ref>PMID:19405910</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+CARM1 is a protein arginine methyltransferase and acts as a transcriptional coactivator regulating multiple biological processes. Aberrant expression of CARM1 has been related to the progression of multiple types of cancers, and therefore CARM1 was considered as a promising drug target. In the present work, we report the structure-based discovery of a series of N(1)-(3-(pyrimidin-2-yl)benzyl)ethane-1,2-diamines as potent CARM1 inhibitors, in which compound 43 displays high potency and selectivity. With the advantage of excellent tissue distribution, compound 43 demonstrated good in vivo efficacy for solid tumors. Furthermore, from the detailed immuno-oncology study with MC38 C57BL/6J xenograft model, we confirmed that this chemical probe 43 has profound effects in tumor immunity, which paves the way for future studies on the modulation of arginine post-translational modification that could be utilized in solid tumor treatment and cancer immunotherapy.
+Structure-Based Discovery of Potent CARM1 Inhibitors for Solid Tumor and Cancer Immunology Therapy.,Zhang Z, Guo Z, Xu X, Cao D, Yang H, Li Y, Shi Q, Du Z, Guo X, Wang X, Chen D, Zhang Y, Chen L, Zhou K, Li J, Geng M, Huang X, Xiong B J Med Chem. 2021 Nov 15. doi: 10.1021/acs.jmedchem.1c01308. PMID:34781683<ref>PMID:34781683</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 7faj" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Cao DY]]
+[[Category: Type I protein arginine methyltransferase]]
-[[Category: Li J]]
+[[Category: Cao, D Y]]
-[[Category: Xiong B]]
+[[Category: Li, J]]
+[[Category: Xiong, B]]
+[[Category: Histone-arginine methyltransferase carm1]]
+[[Category: Transferase]]

7faj

From Proteopedia

Revision as of 10:59, 16 February 2022

CARM1 bound with compound 43

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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