Theoretical Insights into Catalytic Mechanism of Protein Arginine Methyltransferase 1

<div><p>Protein arginine methyltransferase 1 (PRMT1), the major arginine asymmetric dimethylation enzyme in mammals, is emerging as a potential drug target for cancer and cardiovascular disease. Understanding the catalytic mechanism of PRMT1 will facilitate inhibitor design. However, detailed mechanisms of the methyl transfer process and substrate deprotonation of PRMT1 remain unclear. In this study, we present a theoretical study on PRMT1 catalyzed arginine dimethylation by employing molecular dynamics (MD) simulation and quantum mechanics/molecular mechanics (QM/MM) calculation. Ternary complex models, composed of PRMT1, peptide substrate, and S-adenosyl-methionine (AdoMet) as cofactor, were constructed and verified by 30-ns MD simulation. The snapshots selected from the MD trajectory were applied for the QM/MM calculation. The typical S_N2-favored transition states of the first and second methyl transfers were identified from the potential energy profile. Deprotonation of substrate arginine occurs immediately after methyl transfer, and the carboxylate group of E144 acts as proton acceptor. Furthermore, natural bond orbital analysis and electrostatic potential calculation showed that E144 facilitates the charge redistribution during the reaction and reduces the energy barrier. In this study, we propose the detailed mechanism of PRMT1-catalyzed asymmetric dimethylation, which increases insight on the small-molecule effectors design, and enables further investigations into the physiological function of this family. </p> </div

The overall structure of PRMT1-RGG-AdoMet complex and Atoms involved in QM region.

<p>Overall structure of (A) the PRMT1-RGG-AdoMet complex and (B) the microenvironment in active site. Atoms involved in the QM region (stick), and the structure parameters of the PRMT1-RGG-AdoMet complex (C) and the PRMT1-meRGG-AdoMet complex (D).</p

Evolution of the Wiberg bond order during the first methyl transfer.

<p>(A) Illustration of the bond and atom name. (B) The relationship between the formation of OE2-2HH2 and CE-NH2 suggests that deprotonation occurs after methyl transfer. (C) The bond order evolution involved in the guanidino group indicates the charge redistribution during reaction (R: Reactant, TS: S_N2 transition state, P: product)..</p

Proposed PRMT1 Catalytic Mechanism.

<p>Proposed PRMT1 Catalytic Mechanism.</p

Potential Energy Surface of the first (A) and second (B) methyl transfer.

<p>Only the states adjacent to TS were included in the contour plot. Structure of the reactant (R), S_N2 transition state (TS), and product (P) in the first (C) and second (D) methyl transfers.</p

Evolution of electrostatic potential (ESP) charge distribution during the first methyl transfer.

<p>(R: Reactant, TS: S _N2 transition state, P: product).</p

Correction to Anthraquinone Derivatives as Potent Inhibitors of c‑Met Kinase and the Extracellular Signaling Pathway

Correction to Anthraquinone Derivatives as Potent Inhibitors of c‑Met Kinase and the Extracellular Signaling Pathwa

Development of Cell-Active <i>N</i>⁶‑Methyladenosine RNA Demethylase FTO Inhibitor

The direct nucleic acid repair dioxygenase FTO is an enzyme that demethylates <i>N</i>⁶-methyladenosine (m⁶A) residues in mRNA <i>in vitro</i> and inside cells. FTO is the first RNA demethylase discovered that also serves a major regulatory function in mammals. Together with structure-based virtual screening and biochemical analyses, we report the first identification of several small-molecule inhibitors of human FTO demethylase. The most potent compound, the natural product rhein, which is neither a structural mimic of 2-oxoglutarate nor a chelator of metal ion, competitively binds to the FTO active site <i>in vitro</i>. Rhein also exhibits good inhibitory activity on m⁶A demethylation inside cells. These studies shed light on the development of powerful probes and new therapies for use in RNA biology and drug discovery