Uncoupling conformational states from activity in an allosteric enzyme
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João P Pisco Cesira De Chiara Kamila J Pacholarz Acely Garza-Garcia Roksana Ogrodowicz Philip Walker Perdita E Barran Stephen J Smerdon Luiz Pedro CarvalhoAbstract
ATP-phosphoribosyltransferase (ATP-PRT) is a hexameric enzyme in conformational equilibrium between an open and seemingly active state and a closed and presumably inhibited form. The structure-function relationship of allosteric regulation in this system is still not fully understood. Here, we develop a screening strategy for modulators of ATP-PRT and identify 3-(2-thienyl)-l-alanine (TIH) as an allosteric activator of this enzyme. Kinetic analysis reveals co-occupancy of the allosteric sites by TIH and l-histidine. Crystallographic and native ion-mobility mass spectrometry data show that the TIH-bound activated form of the enzyme closely resembles the inhibited l-histidine-bound closed conformation, revealing the uncoupling between ATP-PRT open and closed conformations and its functional state. These findings suggest that dynamic processes are responsible for ATP-PRT allosteric regulation and that similar mechanisms might also be found in other enzymes bearing a ferredoxin-like allosteric domain.
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Journal Nature Communications
Volume 8
Issue number 1
Pages 203
Available online
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Publisher website (DOI) 10.1038/s41467-017-00224-0
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Europe PubMed Central 28781362
Pubmed 28781362
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