Activation by substoichiometric inhibition.
Allosteric Regulation
Allosteric Site
Antineoplastic Agents
/ chemistry
Escherichia coli
Heat-Shock Proteins
/ antagonists & inhibitors
High-Temperature Requirement A Serine Peptidase 1
/ antagonists & inhibitors
Humans
Periplasmic Proteins
/ antagonists & inhibitors
Protease Inhibitors
/ chemistry
Protein Binding
Serine Endopeptidases
/ chemistry
HTRA1
HtrA proteases
allostery
cooperativity
inhibitor
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
21 01 2020
21 01 2020
Historique:
pubmed:
8
1
2020
medline:
24
4
2020
entrez:
8
1
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31907318
pii: 1918721117
doi: 10.1073/pnas.1918721117
pmc: PMC6983408
doi:
Substances chimiques
Antineoplastic Agents
0
Heat-Shock Proteins
0
Periplasmic Proteins
0
Protease Inhibitors
0
DegP protease
EC 3.4.21.-
High-Temperature Requirement A Serine Peptidase 1
EC 3.4.21.-
HTRA1 protein, human
EC 3.4.21.-
Serine Endopeptidases
EC 3.4.21.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1414-1418Déclaration de conflit d'intérêts
The authors declare no competing interest.
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