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dc.contributor.authorThomson, Catherine M.
dc.contributor.authorAlphey, Magnus S.
dc.contributor.authorFisher, Gemma
dc.contributor.authorda Silva, Rafael G
dc.identifier.citationThomson , C M , Alphey , M S , Fisher , G & da Silva , R G 2019 , ' Mapping the structural path for allosteric inhibition of a short-form ATP phosphoribosyltransferase by histidine ' , Biochemistry , vol. 58 , no. 28 , pp. 3078-3086 .
dc.identifier.otherPURE: 259389460
dc.identifier.otherPURE UUID: f4cfc967-4fbf-40b4-b1fb-8a9a068bc2d8
dc.identifier.otherORCID: /0000-0002-1308-8190/work/59953720
dc.identifier.otherWOS: 000476568300005
dc.identifier.otherScopus: 85069868301
dc.identifier.otherORCID: /0000-0002-9353-3716/work/74510015
dc.descriptionFunding: This work was supported by a Wellcome Trust Institutional Strategic Support Fund to the University of St Andrews and the Biotechnology and Biological Sciences Research Council (BBSRC) [grant number BB/M010996/1] via an EASTBIO Doctoral Training Partnership studentship to GF. X-ray diffraction data were collected at Diamond Light Source in the UK.en
dc.description.abstractATP phosphoribosyltransferase (ATPPRT) catalyses 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 (HisGS) and four regulatory subunits (HisZ). HisGS alone is catalytically active and insensitive to histidine. HisZ enhances catalysis by HisGS 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 non-competitive inhibitor of short-form ATPPRT, and that inhibition does not occur by dissociating HisGS from the hetero-octamer. The crystal structure of ATPPRT in complex with histidine and the substrate 5-phospho-α-D-ribosyl-1-pyrophosphate (PRPP) was solved, 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/HisGS interface, and in the absence of histidine its motion prompts HisGS 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-PaHisZ-containing PaATPPRT, 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.
dc.rights© 2019, American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY)License, which permits unrestricted use, distribution and reproduction in any medium,provided the author and source are cited.en
dc.subjectQD Chemistryen
dc.subjectQH301 Biologyen
dc.titleMapping the structural path for allosteric inhibition of a short-form ATP phosphoribosyltransferase by histidineen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews.School of Biologyen
dc.contributor.institutionUniversity of St Andrews.Biomedical Sciences Research Complexen
dc.description.statusPeer revieweden

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