6izq - Revision history

OCA at 10:35, 27 March 2024

OCA — Wed, 27 Mar 2024 10:35:59 GMT

←Older revision		Revision as of 10:35, 27 March 2024
Line 3:		Line 3:
	<StructureSection load='6izq' size='340' side='right'caption='[[6izq]], [[Resolution\|resolution]] 2.45Å' scene=''>		<StructureSection load='6izq' size='340' side='right'caption='[[6izq]], [[Resolution\|resolution]] 2.45Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6izq]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6IZQ OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6IZQ FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6izq]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6IZQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6IZQ FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat">~~<scene name='pdbligand=XJ2:(2R)~~-~~1-(methylamino)-3-(1~~,~~3,4,5-tetrahydro-~~2~~-benzazepin-2-yl)propan-2-ol'>XJ2</scene>~~</td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.449Å</td></tr>
-	<tr id='~~activity~~'><td class="sblockLbl"><b>~~Activity~~:</b></td><td class="sblockDat"><~~span class~~='~~plainlinks'>[http~~:~~//en.wikipedia.org/wiki/Type_I_protein_arginine_methyltransferase Type I protein arginine methyltransferase], with EC number [http://www.brenda~~-~~enzymes.info/php/result_flat.php4?ecno=2.~~1.1~~.319~~ 2~~.1.1.319]~~ </~~span~~></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=XJ2:(2R)-1-(methylamino)-3-(1,3,4,5-tetrahydro-2-benzazepin-2-yl)propan-2-ol'>XJ2</scene></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6izq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6izq OCA], [~~http~~://pdbe.org/6izq PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6izq RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6izq PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6izq ProSAT]</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=6izq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6izq OCA], [https://pdbe.org/6izq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6izq RCSB], [https://www.ebi.ac.uk/pdbsum/6izq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6izq ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://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>	+	[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 ==~~	+
-	PRMT4 is a type I protein arginine methyltransferase and plays important roles in various cellular processes. Overexpression of PRMT4 has been found to be involved in several types of cancers. Selective and in vivo effective PRMT4 inhibitors are needed for demonstrating PRMT4 as a promising therapeutic target. On the basis of compound 6, a weak dual PRMT4/6 inhibitor, we constructed a tetrahydroisoquinoline scaffold through a cut-and-sew scaffold hopping strategy. The subsequent SAR optimization efforts employed structure-based approach led to the identification of a novel PRMT4 inhibitor 49. Compound 49 exhibited prominently high potency and selectivity, moderate pharmacokinetic profiles, and good antitumor efficacy in acute myeloid leukemia xenograft model via oral administration, thus demonstrating this compound as a useful pharmacological tool for further target validation and drug development in cancer therapy.	+

-	Design and Synthesis of Potent, Selective Inhibitors of Protein Arginine Methyltransferase 4 against Acute Myeloid Leukemia.,Guo Z, Zhang Z, Yang H, Cao D, Xu X, Zheng X, Chen D, Wang Q, Li Y, Li J, Du Z, Wang X, Chen L, Ding J, Shen J, Geng M, Huang X, Xiong B J Med Chem. 2019 Jun 13;62(11):5414-5433. doi: 10.1021/acs.jmedchem.9b00297. Epub, 2019 Jun 4. PMID:31117515<ref>PMID:31117515</ref>	+	==See Also==
-		+	*[[Histone methyltransferase 3D structures\|Histone methyltransferase 3D structures]]
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class~~=~~"pdbe-citations 6izq" style~~=~~"background-color:#fffaf0;"></div>~~	+
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Type I protein arginine methyltransferase]]~~	+	[[Category: Cao DY]]
-	[[Category: Cao~~, D Y~~]]	+	[[Category: Guo ZH]]
-	[[Category: Guo~~, Z H~~]]	+	[[Category: Huang X]]
-	[[Category: Huang, X]]	+	[[Category: Li J]]
-	[[Category: Li, J]]	+	[[Category: Li YL]]
-	[[Category: Li~~, Y L~~]]	+	[[Category: Shen JK]]
-	[[Category: Shen~~, J K~~]]	+	[[Category: Xiong B]]
-	[[Category: Xiong, B]]	+
-	~~[[Category: Histone-arginine methyltransferase carm1]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 09:02, 25 December 2019

OCA — Wed, 25 Dec 2019 09:02:30 GMT

←Older revision		Revision as of 09:02, 25 December 2019
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6izq is ~~ON HOLD~~ ~~until Dec 20 2020~~	+	==PRMT4 bound with a bicyclic compound==
		+	<StructureSection load='6izq' size='340' side='right'caption='[[6izq]], [[Resolution\|resolution]] 2.45Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6izq]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6IZQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6IZQ FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=XJ2:(2R)-1-(methylamino)-3-(1,3,4,5-tetrahydro-2-benzazepin-2-yl)propan-2-ol'>XJ2</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Type_I_protein_arginine_methyltransferase Type I protein arginine methyltransferase], with EC number [http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6izq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6izq OCA], [http://pdbe.org/6izq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6izq RCSB], [http://www.ebi.ac.uk/pdbsum/6izq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6izq ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://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 ==
		+	PRMT4 is a type I protein arginine methyltransferase and plays important roles in various cellular processes. Overexpression of PRMT4 has been found to be involved in several types of cancers. Selective and in vivo effective PRMT4 inhibitors are needed for demonstrating PRMT4 as a promising therapeutic target. On the basis of compound 6, a weak dual PRMT4/6 inhibitor, we constructed a tetrahydroisoquinoline scaffold through a cut-and-sew scaffold hopping strategy. The subsequent SAR optimization efforts employed structure-based approach led to the identification of a novel PRMT4 inhibitor 49. Compound 49 exhibited prominently high potency and selectivity, moderate pharmacokinetic profiles, and good antitumor efficacy in acute myeloid leukemia xenograft model via oral administration, thus demonstrating this compound as a useful pharmacological tool for further target validation and drug development in cancer therapy.

-	~~Authors: Xiong~~, B., Cao, D.Y., ~~Guo~~, Z~~.H.~~, Li, Y.L., Li, J., Huang, X~~., Shen~~, J.K.	+	Design and Synthesis of Potent, Selective Inhibitors of Protein Arginine Methyltransferase 4 against Acute Myeloid Leukemia.,Guo Z, Zhang Z, Yang H, Cao D, Xu X, Zheng X, Chen D, Wang Q, Li Y, Li J, Du Z, Wang X, Chen L, Ding J, Shen J, Geng M, Huang X, Xiong B J Med Chem. 2019 Jun 13;62(11):5414-5433. doi: 10.1021/acs.jmedchem.9b00297. Epub, 2019 Jun 4. PMID:31117515<ref>PMID:31117515</ref>

-	~~Description: PRMT4 bound with~~ a ~~bicyclic compound~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
-	[[Category: Cao, D.Y]]	+	<div class="pdbe-citations 6izq" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Type I protein arginine methyltransferase]]
		+	[[Category: Cao, D Y]]
		+	[[Category: Guo, Z H]]
	[[Category: Huang, X]]		[[Category: Huang, X]]
-	[[Category: Xiong, B]]
-	[[Category: Guo, Z.H]]
	[[Category: Li, J]]		[[Category: Li, J]]
-	[[Category: Shen, J.K]]	+	[[Category: Li, Y L]]
-	[[Category: Li, ~~Y.L~~]]	+	[[Category: Shen, J K]]
		+	[[Category: Xiong, B]]
		+	[[Category: Histone-arginine methyltransferase carm1]]
		+	[[Category: Transferase]]

OCA at 06:23, 2 October 2019

OCA — Wed, 02 Oct 2019 06:23:33 GMT

←Older revision		Revision as of 06:23, 2 October 2019
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6izq is ON HOLD	+	The entry 6izq is ON HOLD until Dec 20 2020

	Authors: Xiong, B., Cao, D.Y., Guo, Z.H., Li, Y.L., Li, J., Huang, X., Shen, J.K.		Authors: Xiong, B., Cao, D.Y., Guo, Z.H., Li, Y.L., Li, J., Huang, X., Shen, J.K.
Line 7:		Line 7:
	Description: PRMT4 bound with a bicyclic compound		Description: PRMT4 bound with a bicyclic compound
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Li, J]]
	[[Category: Cao, D.Y]]		[[Category: Cao, D.Y]]
-	[[Category: Shen, J.K]]
	[[Category: Huang, X]]		[[Category: Huang, X]]
	[[Category: Xiong, B]]		[[Category: Xiong, B]]
	[[Category: Guo, Z.H]]		[[Category: Guo, Z.H]]
		+	[[Category: Li, J]]
		+	[[Category: Shen, J.K]]
	[[Category: Li, Y.L]]		[[Category: Li, Y.L]]

OCA at 10:22, 16 January 2019

OCA — Wed, 16 Jan 2019 10:22:53 GMT

←Older revision		Revision as of 10:22, 16 January 2019
Line 3:		Line 3:
	The entry 6izq is ON HOLD		The entry 6izq is ON HOLD

-	Authors: ~~Biong~~, B., Cao, D.Y., Guo, Z.H., Li, Y.L., Li, J., Huang, X., Shen, J.K.	+	Authors: Xiong, B., Cao, D.Y., Guo, Z.H., Li, Y.L., Li, J., Huang, X., Shen, J.K.

	Description: PRMT4 bound with a bicyclic compound		Description: PRMT4 bound with a bicyclic compound
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
		+	[[Category: Li, J]]
	[[Category: Cao, D.Y]]		[[Category: Cao, D.Y]]
-	[[Category: ~~Biong~~, B]]	+	[[Category: Shen, J.K]]
	[[Category: Huang, X]]		[[Category: Huang, X]]
		+	[[Category: Xiong, B]]
	[[Category: Guo, Z.H]]		[[Category: Guo, Z.H]]
-	[[Category: Li, J]]
-	[[Category: Shen, J.K]]
	[[Category: Li, Y.L]]		[[Category: Li, Y.L]]

OCA: Protected "6izq" [edit=sysop:move=sysop]

OCA — Wed, 26 Dec 2018 06:41:47 GMT

Protected "6izq" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:41, 26 December 2018

OCA: New page: '''Unreleased structure''' The entry 6izq is ON HOLD Authors: Biong, B., Cao, D.Y., Guo, Z.H., Li, Y.L., Li, J., Huang, X., Shen, J.K. Description: PRMT4 bound with a bicyclic compound...

OCA — Wed, 26 Dec 2018 06:41:46 GMT

New page: '''Unreleased structure''' The entry 6izq is ON HOLD Authors: Biong, B., Cao, D.Y., Guo, Z.H., Li, Y.L., Li, J., Huang, X., Shen, J.K. Description: PRMT4 bound with a bicyclic compound...

New page

'''Unreleased structure'''

The entry 6izq is ON HOLD

Authors: Biong, B., Cao, D.Y., Guo, Z.H., Li, Y.L., Li, J., Huang, X., Shen, J.K.

Description: PRMT4 bound with a bicyclic compound
[[Category: Unreleased Structures]]
[[Category: Cao, D.Y]]
[[Category: Biong, B]]
[[Category: Huang, X]]
[[Category: Guo, Z.H]]
[[Category: Li, J]]
[[Category: Shen, J.K]]
[[Category: Li, Y.L]]