4HC4

Human HMT1 hnRNP methyltransferase-like protein 6 (S. cerevisiae)

Summary for 4HC4

• Entry DOI: 10.2210/pdb4hc4/pdb
• Descriptor: Protein arginine N-methyltransferase 6, S-ADENOSYL-L-HOMOCYSTEINE, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: hrmt1l6, methyltransferase, s-adenosyl-l-homocysteine, structural genomics, structural genomics consortium, sgc, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus : Q96LA8
• Total number of polymer chains: 1
• Total formula weight: 42613.13

Authors

Dong, A.,Zeng, H.,He, H.,El Bakkouri, M.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,Brown, P.J.,Wu, H.,Structural Genomics Consortium (SGC) (deposition date: 2012-09-28, release date: 2012-10-17, Last modification date: 2024-10-30)

Primary citation

Wu, H.,Zheng, W.,Eram, M.S.,Vhuiyan, M.,Dong, A.,Zeng, H.,He, H.,Brown, P.,Frankel, A.,Vedadi, M.,Luo, M.,Min, J.
Structural basis of arginine asymmetrical dimethylation by PRMT6.
Biochem. J., 473:3049-3063, 2016

PubMed Abstract: PRMT6 is a type I protein arginine methyltransferase, generating the asymmetric dimethylarginine mark on proteins such as histone H3R2. Asymmetric dimethylation of histone H3R2 by PRMT6 acts as a repressive mark that antagonizes trimethylation of H3 lysine 4 by the MLL histone H3K4 methyltransferase. PRMT6 is overexpressed in several cancer types, including prostate, bladder and lung cancers; therefore, it is of great interest to develop potent and selective inhibitors for PRMT6. Here, we report the synthesis of a potent bisubstrate inhibitor GMS [6'-methyleneamine sinefungin, an analog of sinefungin (SNF)], and the crystal structures of human PRMT6 in complex, respectively, with S-adenosyl-L-homocysteine (SAH) and the bisubstrate inhibitor GMS that shed light on the significantly improved inhibition effect of GMS on methylation activity of PRMT6 compared with SAH and an S-adenosyl-L-methionine competitive methyltransferase inhibitor SNF. In addition, we also crystallized PRMT6 in complex with SAH and a short arginine-containing peptide. Based on the structural information here and available in the PDB database, we proposed a mechanism that can rationalize the distinctive arginine methylation product specificity of different types of arginine methyltransferases and pinpoint the structural determinant of such a specificity.

PubMed: 27480107
DOI: 10.1042/BCJ20160537

Experimental method

X-RAY DIFFRACTION (1.97 Å)