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10 Cards in this Set

  • Front
  • Back
Many cellular proteins (like kinases) have similar ligands
We wish to achieve selective activation or inhibition
Orthogonal ligand-receptor pairs
Modify both receptor and ligand to increase specificity
Requirements for constructing an orthogonal receptor-ligand pair
-Structural information about binding site.
-Receptor must tolerate modifications.
-Ability to synthesize orthogonal ligand.

If the native ligand is endogenous, then the receptor also needs to be orthogonal.
How to make an orthogonal ligand/receptor
Manipulate charges

Alter H-bonding patterns

Introduce steric interactions (bump-hole)

~altering affinity is a concern with all methods
manufacturing orthogonality via charge manipulation
1) Charge reversal

2) Removal of a charged interaction

3) Introduction of a new ion pair
Example of "bump-hole" method for kinases
Many kinases are phosphorylated by ATP

-synthesized "bumped" ATP (add group to adenine)

-create "hole" in kinase of interest
Limitation of "bump-hole" method in ATP/Kinase example
“Bumped” ATP analogs cannot enter cells. Thus, cannot identify targets in vivo.

New strategy: use “bumped” cell-permeable kinase inhibitors to allow study of kinases in living cells (Next week’s paper).
A transcriptional regulatory application
Advantage of "bump-hole" method
Bump-hole approach retains temporal control of small molecules while increasing specificity
Disadvantage of "bump-hole" method for therapeutic purposes
Limited direct application to treatment of disease due to requirement for mutation