Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form
As of April 1st VIVO Scientific Profiles will no longer updated for faculty, and the link to VIVO will be removed from the library website. Faculty profile pages will continue to be updated via Interfolio. VIVO will continue being used behind the scenes to update graduate student profiles. Please contact helplib@scripps.edu if you have questions.
How to download citations from VIVO | Alternative profile options

Design of allele-specific protein methyltransferase inhibitors

Academic Article
uri icon
  • Overview
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

authors

  • Lin, Q.
  • Jiang, F. Y.
  • Schultz, Peter
  • Gray, N. S.

publication date

  • November 2001

journal

  • Journal of the American Chemical Society  Journal

abstract

  • Protein arginine methyltransferases, which catalyze the transfer of methyl groups from S-adenosylmethionine (SAM) to arginine side chains in target proteins, regulate transcription, RNA processing, and receptor-mediated signaling. To specifically address the functional role of the individual members of this family, we took a "bump-and-hole" approach and designed a series of N(6)-substituted S-adenosylhomocysteine (SAH) analogues that are targeted toward a yeast protein methyltransferase RMT1. A point mutation was identified (E117G) in Rmt1 that renders the enzyme susceptible to selective inhibition by the SAH analogues. A mass spectrometry based enzymatic assay revealed that two compounds, N(6)-benzyl- and N(6)-naphthylmethyl-SAH, can inhibit the mutant enzyme over the wild-type with the selectivity greater than 20. When the E117G mutation was introduced into the Saccharomyces cerevisiae chromosome, the methylation of Npl3p, a known in vivo Rmt1 substrate, could be moderately reduced by N(6)-naphthylmethyl-SAH in the resulting allele. In addition, an N(6)-benzyl-SAM analogue was found to serve as an orthogonal SAM cofactor. This analogue is preferentially utilized by the mutant methyltransferase relative to the wild-type enzyme with a selectivity greater than 67. This specific enzyme/inhibitor and enzyme/substrate design should be applicable to other members of this protein family and facilitate the characterization of protein methyltransferase function in vivo when combined with RNA expression analysis.

subject areas

  • Alleles
  • Amino Acid Sequence
  • Binding Sites
  • Drug Design
  • Enzyme Inhibitors
  • Kinetics
  • Mutagenesis, Site-Directed
  • Protein Conformation
  • Protein-Arginine N-Methyltransferases
  • S-Adenosylmethionine
  • Saccharomyces cerevisiae
  • Sequence Homology, Amino Acid
  • Substrate Specificity
scroll to property group menus

Identity

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/ja011423j

PubMed ID

  • 11716715
scroll to property group menus

Additional Document Info

start page

  • 11608

end page

  • 11613

volume

  • 123

issue

  • 47

©2022 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support