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2Y1X: Crystal Structure Of Coactivator Associated Arginine Methyltransferase 1 (Carm1) In Complex With Sinefungin And Indole Inhibitor
Biochem. J. (2011)
Coactivator-associated arginine methyltransferase 1 (CARM1) is a protein arginine methyl transferase (PRMT) family member that catalyzes the transfer of methyl groups from S-Adenosyl-L-Methionine to the sidechain 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 like p53. Here we present crystal structures of the CARM1 catalytic domain in complex with cofactors (S-adenosyl-L-homocyseine or 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 isothermal titration calorimetry that the inhibitors bind to the CARM1 catalytic domain only in the presence of the cofactor S-adenosyl-L-homocysteine. Furthermore, sequence differences for select residues that interact with the inhibitors may be responsible for the CARM1 selectivity versus PRMT1 and PRMT3. Together, the structural and biophysical information should aid in the design of both potent and specific inhibitors of CARM1.
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