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Selective Protein Degradation by Ligand‐Targeted Enzymes: Towards the Creation of Catalytic Antagonists
Author(s) -
Davis Benjamin G.,
Sala Rafael F.,
Hodgson David R. W.,
Ullman Astrid,
Khumtaveeporn Kanjai,
Estell David A.,
Sanford Karl,
Bott Richard R.,
Jones J. Bryan
Publication year - 2003
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200300591
Subject(s) - ligand (biochemistry) , homing (biology) , chemistry , enzyme , catalysis , active site , target protein , combinatorial chemistry , biochemistry , computational biology , microbiology and biotechnology , receptor , biology , gene , ecology
Molecular angler fish : By precisely positioning different binding ligands (L) around the active site “mouth” of a degradative proteinase enzyme, target proteins (TP) can be plucked from solution, locked in position adjacent to the catalytic triad “jaws”, and in this way readily and specifically degraded (see scheme). In this strategy, the appropriate ligand acts as a homing device to confer and enhance selectivity, in the best case by more than 350‐fold, in a generic process that exploits the intrinsic, ligand‐recognition capabilities of the protein target to trigger its own destruction. The hunting strategy of the deep sea Angler Fish, which uses a lure above its mouth, illustrates this principle.