Discovery of potent and selective covalent protein arginine methyltransferase (PRMT5) inhibitors

Structure

x-ray diffraction · 2 distinct chains · 21% helix, 34% strand (DSSP).

Ligands and binding sites

• CUX · 2-[[7-[(2~{R},3~{R},4~{S},5~{R})-5-[(~{R})-(4-chlorophenyl)-oxidanyl-methyl]-3,4-bis(oxidanyl) oxolan-2-yl]pyrrolo[2,3-d]pyrimidin-4-yl]amino]ethanal · ligand · chains A
• EDO · 1,2-ethanediol · additive · 7 copies · chains A, B
• DMS · Dimethyl sulfoxide · additive · chains A

Binding sites are the residues within 4.5 Å of a ligand's heavy atoms.

Pockets

7 pockets found on a 1 Å grid, 4 with a druggability of 0.5 or more.

Interfaces

1 interface between chains.

• A–B · 2149 Ų buried · 35 hydrogen bonds · protein-protein

Modifications

Observed in the structure: 1 covalent, 1 disulfide (covalent ligand, disulfide).

Compared structures

• 6K1S · Discovery of Potent and Selective Covalent Protein Arginine Methyltransferase (PRMT5)… · the same entry in another collection · chain A against A, TM-score 1.00
• Q9BQA1 · AlphaFold monomer V2.0 prediction for methylosome protein 50 (Q9BQA1) · a predicted model of the same protein · chain B against A, TM-score 0.99
• O14744 · AlphaFold monomer V2.0 prediction for protein arginine N-methyltransferase 5 (O14744) · a predicted model of the same protein · chain A against A, TM-score 0.97

Analyse

• Open in the research workbench: secondary structure, accessibility, pockets, interfaces, conservation, variants, modifications, peptides and crosslinks on the 3D structure
• Every structure of UniProt O14744
• Every structure of UniProt Q9BQA1
• Elsewhere: RCSB PDB 6K1S · PDBe 6K1S · UniProt O14744 · UniProt Q9BQA1