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Imidazole as a Small Molecule Analogue in Two-Component Signal Transduction.

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Title: Imidazole as a Small Molecule Analogue in Two-Component Signal Transduction.
Authors: Page, Stephani C.1 stephani_page@med.unc.edu, Silversmith, Ruth E.2, Collins, Edward J.1,2, Bourret, Robert B.2
Source: Biochemistry. 12/15/2015, Vol. 54 Issue 49, p7248-7260. 13p.
Subjects: Imidazole analysis, Small molecules, Cellular signal transduction, Histidine kinases, Phosphotransferases, X-ray crystallography, Crystal structure
Abstract: In two-component signal transduction systems (TCSs), responses to stimuli are mediated through phosphotransfer between protein components. Canonical TCSs use His → Asp phosphotransfer in which phosphoryl groups are transferred from a conserved His on a sensory histidine kinase (HK) to a conserved Asp on a response regulator (RR). RRs contain the catalytic core of His → Asp phosphotransfer, evidenced by the ability of RRs to autophosphorylate with small molecule analogues of phospho-His proteins. Phosphorelays are a more complex variation of TCSs that additionally utilize Asp → His phosphotransfer through the use of an additional component, the histidine-containing phosphotransfer domain (Hpt), which reacts with RRs both as phosphodonors and phosphoacceptors. Here we show that imidazole has features of a rudimentary Hpt. Imidazole acted as a nucleophile and attacked phosphorylated RRs (RR-P) to produce monophosphoimidazole (MPI) and unphosphorylated RR. Phosphotransfer from RR-P to imidazole required the intact RR active site, indicating that the RR provided the core catalytic machinery for Asp → His phosphotransfer. Imidazole functioned in an artificial phosphorelay to transfer phosphoryl groups between unrelated RRs. The X-ray crystal structure of an activated RR·imidazole complex showed imidazole oriented in the RR active site similarly to the His of an Hpt. Imidazole interacted with RR nonconserved active site residues, which influenced the relative reactivity of RR-P with imidazole versus water. Rate constants for reaction of imidazole or MPI with chimeric RRs suggested that the RR active site contributes to the kinetic preferences exhibited by the YPD1 Hpt. [ABSTRACT FROM AUTHOR]
Copyright of Biochemistry is the property of American Chemical Society and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Imidazole as a Small Molecule Analogue in Two-Component Signal Transduction.
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  Data: <searchLink fieldCode="AR" term="%22Page%2C+Stephani+C%2E%22">Page, Stephani C.</searchLink><relatesTo>1</relatesTo><i> stephani_page@med.unc.edu</i><br /><searchLink fieldCode="AR" term="%22Silversmith%2C+Ruth+E%2E%22">Silversmith, Ruth E.</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Collins%2C+Edward+J%2E%22">Collins, Edward J.</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Bourret%2C+Robert+B%2E%22">Bourret, Robert B.</searchLink><relatesTo>2</relatesTo>
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  Data: <searchLink fieldCode="JN" term="%22Biochemistry%22">Biochemistry</searchLink>. 12/15/2015, Vol. 54 Issue 49, p7248-7260. 13p.
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  Data: <searchLink fieldCode="DE" term="%22Imidazole+analysis%22">Imidazole analysis</searchLink><br /><searchLink fieldCode="DE" term="%22Small+molecules%22">Small molecules</searchLink><br /><searchLink fieldCode="DE" term="%22Cellular+signal+transduction%22">Cellular signal transduction</searchLink><br /><searchLink fieldCode="DE" term="%22Histidine+kinases%22">Histidine kinases</searchLink><br /><searchLink fieldCode="DE" term="%22Phosphotransferases%22">Phosphotransferases</searchLink><br /><searchLink fieldCode="DE" term="%22X-ray+crystallography%22">X-ray crystallography</searchLink><br /><searchLink fieldCode="DE" term="%22Crystal+structure%22">Crystal structure</searchLink>
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  Data: In two-component signal transduction systems (TCSs), responses to stimuli are mediated through phosphotransfer between protein components. Canonical TCSs use His → Asp phosphotransfer in which phosphoryl groups are transferred from a conserved His on a sensory histidine kinase (HK) to a conserved Asp on a response regulator (RR). RRs contain the catalytic core of His → Asp phosphotransfer, evidenced by the ability of RRs to autophosphorylate with small molecule analogues of phospho-His proteins. Phosphorelays are a more complex variation of TCSs that additionally utilize Asp → His phosphotransfer through the use of an additional component, the histidine-containing phosphotransfer domain (Hpt), which reacts with RRs both as phosphodonors and phosphoacceptors. Here we show that imidazole has features of a rudimentary Hpt. Imidazole acted as a nucleophile and attacked phosphorylated RRs (RR-P) to produce monophosphoimidazole (MPI) and unphosphorylated RR. Phosphotransfer from RR-P to imidazole required the intact RR active site, indicating that the RR provided the core catalytic machinery for Asp → His phosphotransfer. Imidazole functioned in an artificial phosphorelay to transfer phosphoryl groups between unrelated RRs. The X-ray crystal structure of an activated RR·imidazole complex showed imidazole oriented in the RR active site similarly to the His of an Hpt. Imidazole interacted with RR nonconserved active site residues, which influenced the relative reactivity of RR-P with imidazole versus water. Rate constants for reaction of imidazole or MPI with chimeric RRs suggested that the RR active site contributes to the kinetic preferences exhibited by the YPD1 Hpt. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Biochemistry is the property of American Chemical Society and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1021/acs.biochem.5b01082
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      – Code: eng
        Text: English
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        StartPage: 7248
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      – SubjectFull: Imidazole analysis
        Type: general
      – SubjectFull: Small molecules
        Type: general
      – SubjectFull: Cellular signal transduction
        Type: general
      – SubjectFull: Histidine kinases
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      – SubjectFull: Phosphotransferases
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      – SubjectFull: X-ray crystallography
        Type: general
      – SubjectFull: Crystal structure
        Type: general
    Titles:
      – TitleFull: Imidazole as a Small Molecule Analogue in Two-Component Signal Transduction.
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            NameFull: Silversmith, Ruth E.
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            NameFull: Collins, Edward J.
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              Text: 12/15/2015
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              Y: 2015
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