Allosteric inhibition through suppression of transient conformational states

Shiou Ru Tzeng, Charalampos G. Kalodimos

Research output: Contribution to journalArticlepeer-review

87 Scopus citations


The ability to inhibit binding or enzymatic activity is key to preventing aberrant behaviors of proteins. Allosteric inhibition is desirable as it offers several advantages over competitive inhibition, but the mechanisms of action remain poorly understood in most cases. Here we show that allosteric inhibition can be effected by destabilizing a low-populated conformational state that serves as an on-pathway intermediate for ligand binding, without altering the protein's ground-state structure. As standard structural approaches are typically concerned with changes in the ground-state structure of proteins, the presence of such a mechanism can go easily undetected. Our data strongly argue for the routine use of NMR tools suited to detect and characterize transiently formed conformational states in allosteric systems. Structure information on such important intermediates can ultimately result in more efficient design of allosteric inhibitors

Original languageEnglish (US)
Pages (from-to)462-465
Number of pages4
JournalNature Chemical Biology
Issue number7
StatePublished - Jul 2013

Bibliographical note

Funding Information:
This work was supported by the US National Science Foundation grant MCB1121896 to C.G.K.


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