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Uncoupling conformational states from activity in an allosteric enzyme
DOI:
10.1038/s41467-017-00224-0
Authors:
Joao P.
Pisco
(The Francis Crick Institute (Midland Road))
,
Cesira De
Chiara
(The Francis Crick Institute)
,
Kamila J.
Pacholarz
(Manchester Institute of Biotechnology & School of Chemistry, 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
(Manchester Institute of Biotechnology & School of Chemistry, University of Manchester)
,
Stephen J.
Smerdon
(The Francis Crick Institute)
,
Luiz Pedro S. De
Carvalho
(The Francis Crick Institute)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Nature Communications
, VOL 8
State:
Published (Approved)
Published:
August 2017
Diamond Proposal Number(s):
7707
,
9826

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.
Journal Keywords: Enzymes; Screening; Transferases; X-ray crystallography
Subject Areas:
Biology and Bio-materials,
Chemistry
Instruments:
I04-Macromolecular Crystallography
Documents:
s41467-017-00224-0.pdf