Uncoupling conformational states from activity in an allosteric enzyme

João P. Pisco, Cesira de Chiara, Kamila J. Pacholarz, Acely Garza-Garcia, Roksana W. Ogrodowicz, Philip A. Walker, Perdita E. Barran, Stephen J. Smerdon and Luiz Pedro S. de Carvalho ()
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João P. Pisco: The Francis Crick Institute
Cesira de Chiara: The Francis Crick Institute
Kamila J. Pacholarz: University of Manchester
Acely Garza-Garcia: The Francis Crick Institute
Roksana W. Ogrodowicz: The Francis Crick Institute
Philip A. Walker: The Francis Crick Institute
Perdita E. Barran: University of Manchester
Stephen J. Smerdon: The Francis Crick Institute
Luiz Pedro S. de Carvalho: The Francis Crick Institute

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-00224-0

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