A Selective Irreversible Inhibitor Targeting a PDZ Protein Interaction Domain
- 11 September 2003
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 125 (40) , 12074-12075
- https://doi.org/10.1021/ja035540l
Abstract
Irreversible inhibitors of proteases have proven themselves useful tools for determining which proteases are active under given conditions in tissues or cells and for studying the functional role that a protease plays in physiological processes. The application of such techniques to the study of the activity and function of protein−protein interactions has been hindered by the lack of guiding principles for the mechanistic design of irreversible inhibitors targeting the “active site” of a protein interaction. We report herein the first example of a mechanism-based irreversible inhibitor of a protein interaction that has been specifically targeted to one member of the PDZ family of protein interaction domains: the second PDZ domain of the membrane-associated guanylate kinase MAGI3. This inhibitor was designed using rationally directed computational evaluation to take advantage of a conserved histidine in the PDZ domain by introducing an ionizable group that will be held in close proximity to that nucleophile during binding. The novel compound exhibits all of the characteristics of an irreversible inhibitor of the interaction of the tumor suppressor PTEN with MAGI3 in in vitro models. In cells, the inhibitor can be shown to release PTEN from sequestration by MAGI3 and consequently upregulate the PKB signaling pathway.Keywords
This publication has 13 references indexed in Scilit:
- Treatment of Ischemic Brain Damage by Perturbing NMDA Receptor- PSD-95 Protein InteractionsScience, 2002
- Polyunsaturated fatty acid synthesis: what will they think of next?Trends in Biochemical Sciences, 2002
- Chemical Approaches for Functionally Probing the ProteomeMolecular & Cellular Proteomics, 2002
- Ten years of protein kinase B signalling: a hard Akt to followPublished by Elsevier ,2001
- Magi-1cThe Journal of cell biology, 2001
- PDZ Domains and the Organization of Supramolecular ComplexesAnnual Review of Neuroscience, 2001
- PTEN: a tumour suppressor that functions as a phospholipid phosphataseTrends in Cell Biology, 1999
- PDZ domains: fundamental building blocks in the organization of protein complexes at the plasma membraneJournal of Clinical Investigation, 1999
- MAGI-1, a Membrane-associated Guanylate Kinase with a Unique Arrangement of Protein-Protein Interaction DomainsJournal of Biological Chemistry, 1997
- Crystal Structures of a Complexed and Peptide-Free Membrane Protein–Binding Domain: Molecular Basis of Peptide Recognition by PDZCell, 1996