Abstract
Startling reports described the paradoxical triggering of the human mitogen-activated protein kinase pathway when a small-molecule inhibitor specifically inactivates the BRAF V600E protein kinase but not wt-BRAF. We performed a conceptual analysis of the general phenomenon "activation by inhibition" using bacterial and human HtrA proteases as models. Our data suggest a clear explanation that is based on the classic biochemical principles of allostery and cooperativity. Although substoichiometric occupancy of inhibitor binding sites results in partial inhibition, this effect is overrun by a concomitant activation of unliganded binding sites. Therefore, when an inhibitor of a cooperative enzyme does not reach saturating levels, a common scenario during drug administration, it may cause the contrary of the desired effect. The implications for drug development are discussed.
Keywords:
HTRA1; HtrA proteases; allostery; cooperativity; inhibitor.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Allosteric Regulation
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Allosteric Site*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Escherichia coli
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Heat-Shock Proteins / antagonists & inhibitors*
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Heat-Shock Proteins / chemistry
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Heat-Shock Proteins / metabolism
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High-Temperature Requirement A Serine Peptidase 1 / antagonists & inhibitors*
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High-Temperature Requirement A Serine Peptidase 1 / chemistry
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High-Temperature Requirement A Serine Peptidase 1 / metabolism
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Humans
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Periplasmic Proteins / antagonists & inhibitors*
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Periplasmic Proteins / chemistry
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Periplasmic Proteins / metabolism
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology*
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Protein Binding
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Serine Endopeptidases / chemistry
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Serine Endopeptidases / metabolism
Substances
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Antineoplastic Agents
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Heat-Shock Proteins
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Periplasmic Proteins
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Protease Inhibitors
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DegP protease
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High-Temperature Requirement A Serine Peptidase 1
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HTRA1 protein, human
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Serine Endopeptidases