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==CRYSTAL STRUCTURE OF COACTIVATOR ASSOCIATED ARGININE METHYLTRANSFERASE 1 (CARM1) IN COMPLEX WITH SINEFUNGIN AND INDOLE INHIBITOR== | |||
<StructureSection load='2y1x' size='340' side='right' caption='[[2y1x]], [[Resolution|resolution]] 2.40Å' scene=''> | |||
{ | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2y1x]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Y1X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2Y1X FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=845:N-(3-{5-[5-(1H-INDOL-4-YL)-1,3,4-OXADIAZOL-2-YL]-3-(TRIFLUOROMETHYL)-1H-PYRAZOL-1-YL}BENZYL)-L-ALANINAMIDE'>845</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2y1w|2y1w]]</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone-arginine_N-methyltransferase Histone-arginine N-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.125 2.1.1.125] </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=2y1x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2y1x OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2y1x RCSB], [http://www.ebi.ac.uk/pdbsum/2y1x PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
CARM1 (co-activator-associated arginine methyltransferase 1) is a PRMT (protein arginine N-methyltransferase) family member that catalyses the transfer of methyl groups from SAM (S-adenosylmethionine) to the side chain of specific arginine residues of substrate proteins. This post-translational modification of proteins regulates a variety of transcriptional events and other cellular processes. Moreover, CARM1 is a potential oncological target due to its multiple roles in transcription activation by nuclear hormone receptors and other transcription factors such as p53. Here, we present crystal structures of the CARM1 catalytic domain in complex with cofactors [SAH (S-adenosyl-L-homocysteine) or SNF (sinefungin)] and indole or pyazole inhibitors. Analysis of the structures reveals that the inhibitors bind in the arginine-binding cavity and the surrounding pocket that exists at the interface between the N- and C-terminal domains. In addition, we show using ITC (isothermal titration calorimetry) that the inhibitors bind to the CARM1 catalytic domain only in the presence of the cofactor SAH. Furthermore, sequence differences for select residues that interact with the inhibitors may be responsible for the CARM1 selectivity against PRMT1 and PRMT3. Together, the structural and biophysical information should aid in the design of both potent and specific inhibitors of CARM1. | |||
Structural basis for CARM1 inhibition by indole and pyrazole inhibitors.,Sack JS, Thieffine S, Bandiera T, Fasolini M, Duke GJ, Jayaraman L, Kish KF, Klei HE, Purandare AV, Rosettani P, Troiani S, Xie D, Bertrand JA Biochem J. 2011 Jun 1;436(2):331-9. PMID:21410432<ref>PMID:21410432</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== | ==See Also== | ||
*[[Histone methyltransferase|Histone methyltransferase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Histone-arginine N-methyltransferase]] | [[Category: Histone-arginine N-methyltransferase]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Bandiera, T | [[Category: Bandiera, T]] | ||
[[Category: Bertrand, J A | [[Category: Bertrand, J A]] | ||
[[Category: Duke, G J | [[Category: Duke, G J]] | ||
[[Category: Fasolini, M | [[Category: Fasolini, M]] | ||
[[Category: Jayaraman, L | [[Category: Jayaraman, L]] | ||
[[Category: Kish, K F | [[Category: Kish, K F]] | ||
[[Category: Klei, H E | [[Category: Klei, H E]] | ||
[[Category: Purandare, A V | [[Category: Purandare, A V]] | ||
[[Category: Rosettani, P | [[Category: Rosettani, P]] | ||
[[Category: Sack, J S | [[Category: Sack, J S]] | ||
[[Category: Thieffine, S | [[Category: Thieffine, S]] | ||
[[Category: Troiani, S | [[Category: Troiani, S]] | ||
[[Category: Xie, D | [[Category: Xie, D]] | ||
[[Category: Histone modification]] | [[Category: Histone modification]] | ||
[[Category: Transferase]] | [[Category: Transferase]] | ||
Revision as of 17:01, 18 December 2014
CRYSTAL STRUCTURE OF COACTIVATOR ASSOCIATED ARGININE METHYLTRANSFERASE 1 (CARM1) IN COMPLEX WITH SINEFUNGIN AND INDOLE INHIBITORCRYSTAL STRUCTURE OF COACTIVATOR ASSOCIATED ARGININE METHYLTRANSFERASE 1 (CARM1) IN COMPLEX WITH SINEFUNGIN AND INDOLE INHIBITOR
Structural highlights
Publication Abstract from PubMedCARM1 (co-activator-associated arginine methyltransferase 1) is a PRMT (protein arginine N-methyltransferase) family member that catalyses the transfer of methyl groups from SAM (S-adenosylmethionine) to the side chain of specific arginine residues of substrate proteins. This post-translational modification of proteins regulates a variety of transcriptional events and other cellular processes. Moreover, CARM1 is a potential oncological target due to its multiple roles in transcription activation by nuclear hormone receptors and other transcription factors such as p53. Here, we present crystal structures of the CARM1 catalytic domain in complex with cofactors [SAH (S-adenosyl-L-homocysteine) or SNF (sinefungin)] and indole or pyazole inhibitors. Analysis of the structures reveals that the inhibitors bind in the arginine-binding cavity and the surrounding pocket that exists at the interface between the N- and C-terminal domains. In addition, we show using ITC (isothermal titration calorimetry) that the inhibitors bind to the CARM1 catalytic domain only in the presence of the cofactor SAH. Furthermore, sequence differences for select residues that interact with the inhibitors may be responsible for the CARM1 selectivity against PRMT1 and PRMT3. Together, the structural and biophysical information should aid in the design of both potent and specific inhibitors of CARM1. Structural basis for CARM1 inhibition by indole and pyrazole inhibitors.,Sack JS, Thieffine S, Bandiera T, Fasolini M, Duke GJ, Jayaraman L, Kish KF, Klei HE, Purandare AV, Rosettani P, Troiani S, Xie D, Bertrand JA Biochem J. 2011 Jun 1;436(2):331-9. PMID:21410432[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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