6R02

Psychrobacter arcticus ATP phosphoribosyltransferase bound to histidine and PRPP

Summary for 6R02

• Entry DOI: 10.2210/pdb6r02/pdb
• Descriptor: ATP phosphoribosyltransferase regulatory subunit, ATP phosphoribosyltransferase, HISTIDINE, ... (5 entities in total)
• Functional Keywords: atpprt, histidine, phosphoribosyltransferase, transferase
• Biological source: Psychrobacter arcticus; More
• Total number of polymer chains: 8
• Total formula weight: 275664.94

Authors

Alphey, M.S.,da Silva, R.G.,Thomson, C.M. (deposition date: 2019-03-12, release date: 2019-08-07, Last modification date: 2024-01-24)

Primary citation

Thomson, C.M.,Alphey, M.S.,Fisher, G.,da Silva, R.G.
Mapping the Structural Path for Allosteric Inhibition of a Short-Form ATP Phosphoribosyltransferase by Histidine.
Biochemistry, 58:3078-3086, 2019

PubMed Abstract: ATP phosphoribosyltransferase (ATPPRT) catalyzes the first step of histidine biosynthesis, being allosterically inhibited by the final product of the pathway. Allosteric inhibition of long-form ATPPRTs by histidine has been extensively studied, but inhibition of short-form ATPPRTs is poorly understood. Short-form ATPPRTs are hetero-octamers formed by four catalytic subunits (HisG) and four regulatory subunits (HisZ). HisG alone is catalytically active and insensitive to histidine. HisZ enhances catalysis by HisG in the absence of histidine but mediates allosteric inhibition in its presence. Here, steady-state and pre-steady-state kinetics establish that histidine is a noncompetitive inhibitor of short-form ATPPRT and that inhibition does not occur by dissociating HisG from the hetero-octamer. The crystal structure of ATPPRT in complex with histidine and the substrate 5-phospho-α-d-ribosyl-1-pyrophosphate was determined, showing histidine bound solely to HisZ, with four histidine molecules per hetero-octamer. Histidine binding involves the repositioning of two HisZ loops. The histidine-binding loop moves closer to histidine to establish polar contacts. This leads to a hydrogen bond between its Tyr263 and His104 in the Asp101-Leu117 loop. The Asp101-Leu117 loop leads to the HisZ-HisG interface, and in the absence of histidine, its motion prompts HisG conformational changes responsible for catalytic activation. Following histidine binding, interaction with the histidine-binding loop may prevent the Asp101-Leu117 loop from efficiently sampling conformations conducive to catalytic activation. Tyr263Phe-HisZ-containing ATPPRT, however, is less susceptible though not insensitive to histidine inhibition, suggesting the Tyr263-His104 interaction may be relevant to yet not solely responsible for transmission of the allosteric signal.

PubMed: 31251578
DOI: 10.1021/acs.biochem.9b00282

Experimental method

X-RAY DIFFRACTION (2.65 Å)