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An allosteric inhibitor of protein arginine methyltransferase 3

Alena Siarheyeva1, Guillermo Senisterra, Abdellah Allali-Hassani

  • 1Structural Genomics Consortium, University of Toronto, 101 College Street, MaRS Centre, South Tower, Toronto, ON M5G 1L7, Canada.

Structure (London, England : 1993)
|July 17, 2012
PubMed

Insights

Researchers identified a novel inhibitor for protein arginine methyltransferase 3 (PRMT3), revealing an allosteric inhibition mechanism. This discovery targets PRMT3, an emerging therapeutic target for various diseases.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Protein arginine methyltransferase 3 (PRMT3) is involved in ribosomal biosynthesis.
  • PRMT3 catalyzes the dimethylation of the 40S ribosomal protein S2.
  • PRMT3 exhibits in vitro methyltransferase activity on histone H4 peptide (H4 1-24).

Purpose of the Study:

  • To identify inhibitors of PRMT3.
  • To elucidate the mechanism of PRMT3 inhibition.
  • To explore PRMT3 as a therapeutic target.

Main Methods:

  • Screening of 16,000 compounds using H4 (1-24) peptide as a substrate.
  • Biochemical assays to determine IC50 values.
  • Crystal structure determination of PRMT3 in complex with the inhibitor.
  • Kinetic analysis and site-directed mutagenesis.

Main Results:

  • Identification of a PRMT3 inhibitor (compound 1) with an IC50 of 2.5 μM.
  • The crystal structure and kinetic data revealed an allosteric mechanism of inhibition.
  • Mutations in the allosteric site or analogs disrupting allosteric interactions abolished PRMT3 inhibition.

Conclusions:

  • PRMT3 can be allosterically inhibited.
  • This study demonstrates a novel allosteric inhibition mechanism for protein arginine methyltransferases.
  • PRMT3 represents a promising therapeutic target, with allosteric inhibitors offering a new avenue for drug development.

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