ArticleCommunications biology2022
Cryo-EM structure-based selection of computed ligand poses enables design of MTA-synergic PRMT5 inhibitors of better potency.
Article in Communications biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 10 citations in OpenAlex.
- Article
- Affinity purification contaminants identified by cryo-EM and mass spectrometry.Bioscience reports · 2026Article
- Using Cryogenic Electron Tomography (cryoET) to Determine Rubisco Polymerization Constants in α-Carboxysomes.bioRxiv : the preprint server for biology · 2026Article
- Developments and challenges in hit progression within fragment-based drug discovery.Nature communications · 2026Review
- Protein arginine methyltransferases in cardiovascular disease: mechanisms, therapeutic potential, and future directions.Frontiers in physiology · 2026Review
- Combining Cryo-EM with Computational Approaches To Revolutionize Structural Biology.The protein journal · 2025Review
- Discovery and Mechanism of 16-19F, a Novel Synthetic Lethal Inhibitor of the PRMT5•MTA Complex in MTAP-Deleted Cancer Cells.ACS chemical biology · 2025Article
- DockEM: an enhanced method for atomic-scale protein-ligand docking refinement leveraging low-to-medium resolution cryo-EM density maps.Briefings in bioinformatics · 2025Article
- EMICSS: added-value annotations for EMDB entries.Bioinformatics advances · 2025Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
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.
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