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TitleCryo-EM structure-based selection of computed ligand poses enables design of MTA-synergic PRMT5 inhibitors of better potency.
Journal, issue, pagesCommun Biol, Vol. 5, Issue 1, Page 1054, Year 2022
Publish dateOct 3, 2022
AuthorsWei Zhou / Gaya P Yadav / Xiaozhi Yang / Feng Qin / Chenglong Li / Qiu-Xing Jiang /
PubMed AbstractProjected 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 ...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.
External linksCommun Biol / PubMed:36192627 / PubMed Central
MethodsEM (single particle)
Resolution3.14 Å
Structure data

27078

8cyi

EMDB-27078, PDB-8cyi:
Cryo-EM structures and computational analysis for enhanced potency in MTA-synergic inhibition of human protein arginine methyltransferase 5
Method: EM (single particle) / Resolution: 3.14 Å

Chemicals

ChemComp-P2R:
N-[(2-aminoquinolin-7-yl)methyl]-9-(2-hydroxyethyl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide

ChemComp-MTA:
5'-DEOXY-5'-METHYLTHIOADENOSINE

Source
  • homo sapiens (human)
KeywordsONCOPROTEIN/Transferase / 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

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