2Y1X

CRYSTAL STRUCTURE OF COACTIVATOR ASSOCIATED ARGININE METHYLTRANSFERASE 1 (CARM1) IN COMPLEX WITH SINEFUNGIN AND INDOLE INHIBITOR

Summary for 2Y1X

• Entry DOI: 10.2210/pdb2y1x/pdb
• Related: 2Y1W
• Descriptor: HISTONE-ARGININE METHYLTRANSFERASE CARM1, S-ADENOSYL-L-HOMOCYSTEINE, N-(3-{5-[5-(1H-INDOL-4-YL)-1,3,4-OXADIAZOL-2-YL]-3-(TRIFLUOROMETHYL)-1H-PYRAZOL-1-YL}BENZYL)-L-ALANINAMIDE, ... (5 entities in total)
• Functional Keywords: histone modification, transferase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Nucleus: Q86X55
• Total number of polymer chains: 4
• Total formula weight: 161588.98

Authors

Sack, J.S.,Thieffine, S.,Bandiera, T.,Fasolini, M.,Duke, G.J.,Jayaraman, L.,Kish, K.F.,Klei, H.E.,Purandare, A.V.,Rosettani, P.,Troiani, S.,Xie, D.,Bertrand, J.A. (deposition date: 2010-12-10, release date: 2011-03-23, Last modification date: 2024-05-01)

Primary citation

Sack, J.S.,Thieffine, S.,Bandiera, T.,Fasolini, M.,Duke, G.J.,Jayaraman, L.,Kish, K.F.,Klei, H.E.,Purandare, A.V.,Rosettani, P.,Troiani, S.,Xie, D.,Bertrand, J.A.
Structural Basis for Carm1 Inhibition by Indole and Pyrazole Inhibitors
Biochem.J., 436:331-, 2011

PubMed Abstract: 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.

PubMed: 21410432
DOI: 10.1042/BJ20102161

Experimental method

X-RAY DIFFRACTION (2.4 Å)