Cryo-EM structure-based selection of computed ligand poses enables design of MTA-synergic PRMT5 inhibitors of better potency
Year: 2022
Type: article
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.
Source: Communications Biology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,490
Funders: Simons Foundation, Cystic Fibrosis Foundation, Purdue University, Florida State University, Case Western Reserve University, Frederick National Laboratory for Cancer Research, Tsinghua University, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, Common Fund
Awards: G1567773112, G2039066037, Mechanisms of Heat Sensing by Nociceptive Vanilloid Receptors, G411694581, Molecular Mechanisms of the RNAi/MicroRNA Pathways, G5180746624, The Southeastern Consortium for Microscopy of MacroMolecular Machines, Structural study of a Kv channel in different conformations in membranes, Midwest Consortium for High Resolution Cryoelectron Microscopy, G6743207394, Chemically engineered bilayers for cryoEM imaging of membrane proteins in continuous membranes, G7229056886, G7373107547, NCCAT: National Center for CryoEM Access and Training, Role and targeting of PRMT5 in prostate cancer
OpenAlex ID: W4300772878