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10 Cards in this Set
- Front
- Back
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Many cellular proteins (like kinases) have similar ligands
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We wish to achieve selective activation or inhibition
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Orthogonal ligand-receptor pairs
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Modify both receptor and ligand to increase specificity
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Requirements for constructing an orthogonal receptor-ligand pair
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-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. |
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How to make an orthogonal ligand/receptor
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Manipulate charges
Alter H-bonding patterns Introduce steric interactions (bump-hole) ~altering affinity is a concern with all methods |
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manufacturing orthogonality via charge manipulation
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1) Charge reversal
2) Removal of a charged interaction 3) Introduction of a new ion pair |
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Example of "bump-hole" method for kinases
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Many kinases are phosphorylated by ATP
-synthesized "bumped" ATP (add group to adenine) -create "hole" in kinase of interest |
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Limitation of "bump-hole" method in ATP/Kinase example
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“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). |
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A transcriptional regulatory application
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Advantage of "bump-hole" method
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Bump-hole approach retains temporal control of small molecules while increasing specificity
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Disadvantage of "bump-hole" method for therapeutic purposes
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Limited direct application to treatment of disease due to requirement for mutation
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