{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Merdanovic M"],"funding":["Deutsche Forschungsgemeinschaft"],"pagination":["1414-1418"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6983408"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["117(3)"],"pubmed_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."],"journal":["Proceedings of the National Academy of Sciences of the United States of America"],"pubmed_title":["Activation by substoichiometric inhibition."],"pmcid":["PMC6983408"],"funding_grant_id":["CRC1093"],"pubmed_authors":["Knapp S","Merdanovic M","Huber R","Burston SG","Clausen T","Kocher S","Ehrmann M","Schmitz AL","Kaiser M"],"additional_accession":[]},"is_claimable":false,"name":"Activation by substoichiometric inhibition.","description":"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.","dates":{"release":"2020-01-01T00:00:00Z","publication":"2020 Jan","modification":"2024-02-15T21:47:39.856Z","creation":"2020-07-09T07:01:22Z"},"accession":"S-EPMC6983408","cross_references":{"pubmed":["31907318"],"doi":["10.1073/pnas.1918721117"]}}