8CYI

Cryo-EM structures and computational analysis for enhanced potency in MTA-synergic inhibition of human protein arginine methyltransferase 5

Summary for 8CYI

• Entry DOI: 10.2210/pdb8cyi/pdb
• EMDB information: 27078
• Descriptor: Protein arginine N-methyltransferase 5, Methylosome protein 50, N-[(2-aminoquinolin-7-yl)methyl]-9-(2-hydroxyethyl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide, ... (4 entities in total)
• Functional Keywords: prmt5, protein arginine methyl transferase, mta-inhibitor synergy, cryo-em structure-based drug design, computational analysis, catalytic mechanism, drug discovery, docking analysis, oncoprotein, oncoprotein-transferase complex, oncoprotein/transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 106704.71

Authors

Yadav, G.P.,Wei, Z.,Xiaozhi, Y.,Chenglong, L.,Jiang, Q. (deposition date: 2022-05-23, release date: 2023-04-12, Last modification date: 2024-06-12)

Primary citation

Zhou, W.,Yadav, G.P.,Yang, X.,Qin, F.,Li, C.,Jiang, Q.X.
Cryo-EM structure-based selection of computed ligand poses enables design of MTA-synergic PRMT5 inhibitors of better potency.
Commun Biol, 5:1054-1054, 2022

PubMed Abstract: Projected potential of 2.5-4.0 Å cryo-EM structures for structure-based drug design is not well realized yet. Here we show that a 3.1 Å structure of PRMT5 is suitable for selecting computed poses of a chemical inhibitor and its analogs for enhanced potency. PRMT5, an oncogenic target for various cancer types, has many inhibitors manifesting little cooperativity with MTA, a co-factor analog accumulated in MTAP-/- cells. To achieve MTA-synergic inhibition, a pharmacophore from virtual screen leads to a specific inhibitor (11-2 F). Cryo-EM structures of 11-2 F / MTA-bound human PRMT5/MEP50 complex and its apo form resolved at 3.1 and 3.2 Å respectively show that 11-2 F in the catalytic pocket shifts the cofactor-binding pocket away by ~2.0 Å, contributing to positive cooperativity. Computational analysis predicts subtype specificity of 11-2 F among PRMTs. Structural analysis of ligands in the binding pockets is performed to compare poses of 11-2 F and its redesigned analogs and identifies three new analogs predicted to have significantly better potency. One of them, after synthesis, is ~4 fold more efficient in inhibiting PRMT5 catalysis than 11-2 F, with strong MTA-synergy. These data suggest the feasibility of employing near-atomic resolution cryo-EM structures and computational analysis of ligand poses for small molecule therapeutics.

PubMed: 36192627
DOI: 10.1038/s42003-022-03991-9

Experimental method

ELECTRON MICROSCOPY (3.14 Å)