Dataset Information

Structure-Based Design of Inhibitors of the m⁶A-RNA Writer Enzyme METTL3.

ABSTRACT: Methyltransferase-like 3 (METTL3) and METTL14 form a heterodimeric complex that catalyzes the most abundant internal mRNA modification, N⁶-methyladenosine (m⁶A). METTL3 is the catalytic subunit that binds the co-substrate S-adenosyl methionine (SAM), while METTL14 is involved in mRNA binding. The m⁶A modification provides post-transcriptional level control over gene expression as it affects almost all stages of the mRNA life cycle, including splicing, nuclear export, translation, and decay. There is increasing evidence for an oncogenic role of METTL3 in acute myeloid leukemia. Here, we use structural and dynamic details of the catalytic subunit METTL3 for developing small-molecule inhibitors that compete with SAM. Starting from a hit identified by high-throughput docking, protein crystallography and molecular dynamics simulations were employed to guide the optimization of inhibitory activity. The potency was successfully improved by 8000-fold as measured by a homogeneous time-resolved fluorescence assay. The optimized compound is selective against the off-targets RNA methyltransferases METTL1 and METTL16.

SUBMITTER: Bedi RK

PROVIDER: S-EPMC10436262 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Structure-Based Design of Inhibitors of the m6A-RNA Writer Enzyme METTL3.

Bedi Rajiv Kumar RK Huang Danzhi D Li Yaozong Y Caflisch Amedeo A

ACS bio & med chem Au 20230614 4

Methyltransferase-like 3 (METTL3) and METTL14 form a heterodimeric complex that catalyzes the most abundant internal mRNA modification, N6-methyladenosine (m6A). METTL3 is the catalytic subunit that binds the co-substrate S-adenosyl methionine (SAM), while METTL14 is involved in mRNA binding. The m6A modification provides post-transcriptional level control over gene expression as it affects almost all stages of the mRNA life cycle, including splicin ...[more]

PMID: 37599794

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Project description:KRAS has long been referred to as an 'undruggable' target due to its high affinity for its cognate ligands (GDP and GTP) and its lack of readily exploited allosteric binding pockets. Recent progress in the development of covalent inhibitors of KRASG12C has revealed that occupancy of an allosteric binding site located between the α3-helix and switch-II loop of KRASG12C-sometimes referred to as the 'switch-II pocket'-holds great potential in the design of direct inhibitors of KRASG12C. In studying diverse switch-II pocket binders during the development of sotorasib (AMG 510), the first FDA-approved inhibitor of KRASG12C, we found the dramatic conformational flexibility of the switch-II pocket posing significant challenges toward the structure-based design of inhibitors. Here, we present our computational approaches for dealing with receptor flexibility in the prediction of ligand binding pose and binding affinity. For binding pose prediction, we modified the covalent docking program CovDock to allow for protein conformational mobility. This new docking approach, termed as FlexCovDock, improves success rates from 55 to 89% for binding pose prediction on a dataset of 10 cross-docking cases and has been prospectively validated across diverse ligand chemotypes. For binding affinity prediction, we found standard free energy perturbation (FEP) methods could not adequately handle the significant conformational change of the switch-II loop. We developed a new computational strategy to accelerate conformational transitions through the use of targeted protein mutations. Using this methodology, the mean unsigned error (MUE) of binding affinity prediction were reduced from 1.44 to 0.89 kcal/mol on a set of 14 compounds. These approaches were of significant use in facilitating the structure-based design of KRASG12C inhibitors and are anticipated to be of further use in the design of covalent (and noncovalent) inhibitors of other conformationally labile protein targets.

Dataset Information

Structure-Based Design of Inhibitors of the m⁶A-RNA Writer Enzyme METTL3.

Publications

Structure-Based Design of Inhibitors of the m<sup>6</sup>A-RNA Writer Enzyme METTL3.

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