期刊
NATURE COMMUNICATIONS
卷 8, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-00224-0
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资金
- Francis Crick Institute from Cancer Research UK [FC001060]
- UK Medical Research Council [FC001060]
- Wellcome Trust [FC001060]
- Diamond Light Source [7707, 9826]
- BBSRC [BB/L002655/1] Funding Source: UKRI
- MRC [MC_U117533887, MC_U117584228] Funding Source: UKRI
- Medical Research Council [1254166, MC_U117584228, MC_U117533887, 1365262, U117531954] Funding Source: researchfish
- The Francis Crick Institute [10156, 10060, 10029] Funding Source: researchfish
- The Francis Crick Institute
- Cancer Research UK [10015] Funding Source: researchfish
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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