3SMQ

Crystal structure of protein arginine methyltransferase 3

Summary for 3SMQ

• Entry DOI: 10.2210/pdb3smq/pdb
• Descriptor: Protein arginine N-methyltransferase 3, 1-(1,2,3-benzothiadiazol-6-yl)-3-[2-(cyclohex-1-en-1-yl)ethyl]urea, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: structural genomics, structural genomics consortium, sgc, prmt3, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: O60678
• Total number of polymer chains: 1
• Total formula weight: 38619.76

Authors

Dobrovetsky, E.,Dong, A.,Walker, J.R.,Siarheyeva, A.,Senisterra, G.,Wasney, G.A.,Smil, D.,Bolshan, Y.,Nguyen, K.T.,Allali-Hassani, A.,Hajian, T.,Poda, G.,Bountra, C.,Weigelt, J.,Edwards, A.M.,Al-Awar, R.,Brown, P.J.,Schapira, M.,Arrowsmith, C.H.,Vedadi, M.,Structural Genomics Consortium (SGC) (deposition date: 2011-06-28, release date: 2011-08-31, Last modification date: 2023-09-13)

Primary citation

Siarheyeva, A.,Senisterra, G.,Allali-Hassani, A.,Dong, A.,Dobrovetsky, E.,Wasney, G.A.,Chau, I.,Marcellus, R.,Hajian, T.,Liu, F.,Korboukh, I.,Smil, D.,Bolshan, Y.,Min, J.,Wu, H.,Zeng, H.,Loppnau, P.,Poda, G.,Griffin, C.,Aman, A.,Brown, P.J.,Jin, J.,Al-Awar, R.,Arrowsmith, C.H.,Schapira, M.,Vedadi, M.
An allosteric inhibitor of protein arginine methyltransferase 3.
Structure, 20:1425-1435, 2012

PubMed Abstract: PRMT3, a protein arginine methyltransferase, has been shown to influence ribosomal biosynthesis by catalyzing the dimethylation of the 40S ribosomal protein S2. Although PRMT3 has been reported to be a cytosolic protein, it has been shown to methylate histone H4 peptide (H4 1-24) in vitro. Here, we report the identification of a PRMT3 inhibitor (1-(benzo[d][1,2,3]thiadiazol-6-yl)-3-(2-cyclohexenylethyl)urea; compound 1) with IC50 value of 2.5 μM by screening a library of 16,000 compounds using H4 (1-24) peptide as a substrate. The crystal structure of PRMT3 in complex with compound 1 as well as kinetic analysis reveals an allosteric mechanism of inhibition. Mutating PRMT3 residues within the allosteric site or using compound 1 analogs that disrupt interactions with allosteric site residues both abrogated binding and inhibitory activity. These data demonstrate an allosteric mechanism for inhibition of protein arginine methyltransferases, an emerging class of therapeutic targets.

PubMed: 22795084
DOI: 10.1016/j.str.2012.06.001

Experimental method

X-RAY DIFFRACTION (2 Å)