5LHU

ATP Phosphoribosyltransferase from Mycobacterium tuberculosis in complex with the allosteric inhibitor L-Histidine

Summary for 5LHU

• Entry DOI: 10.2210/pdb5lhu/pdb
• Descriptor: ATP phosphoribosyltransferase, HISTIDINE, SULFATE ION, ... (5 entities in total)
• Functional Keywords: atp-prtase, act, his g, histidine biosynthesis, transferase
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• Total number of polymer chains: 1
• Total formula weight: 32510.66

Authors

de Chiara, C.,Pisco, J.P.,de Carvalho, L.P.,Smerdon, S.J.,Walker, P.A.,Ogrodowicz, R. (deposition date: 2016-07-12, release date: 2017-06-21, Last modification date: 2024-10-23)

Primary citation

Pisco, J.P.,Chiara, C.,Pacholarz, K.J.,Garza-Garcia, A.,Ogrodowicz, R.W.,Walker, P.A.,Barran, P.E.,Smerdon, S.J.,Carvalho, L.P.S.
Uncoupling conformational states from activity in an allosteric enzyme.
Nat Commun, 8:203-203, 2017

PubMed 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.Active and inactive state ATP-phosphoribosyltransferases (ATP-PRTs) are believed to have different conformations. Here the authors show that in both states, ATP-PRT has a similar structural arrangement, suggesting that dynamic alterations are involved in ATP-PRT regulation by allosteric modulators.

PubMed: 28781362
DOI: 10.1038/s41467-017-00224-0

Experimental method

X-RAY DIFFRACTION (2.02 Å)