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P2X receptors: dawn of the post-structure era.

Young MT - Trends Biochem. Sci. (2009)

Bottom Line: P2X receptors are non-selective cation channels gated by extracellular ATP.The recent report of the three-dimensional (3D) crystal structure of zebrafish P2X4.1 represents a step change in our understanding of these membrane ion channels, where previously only low-resolution structural data and inferences from indirect structure-function studies were available.The purpose of this review is to place previous work within the context of the new 3D structure, and to summarize the key questions and challenges which await P2X researchers as we move into the post-structure era.

View Article: PubMed Central - PubMed

Affiliation: School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, United Kingdom. YoungMT@cardiff.ac.uk

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Representations of the ΔzfP2X4.1 structure. The first P2X receptor structure provides a wealth of new information about the overall fold of the molecule, subunit–subunit interactions, and hints at the location of the ATP binding site. Regions of amino acid sequence (a) contributing to each domain within the ΔzfP2X4.1 crystal structure are shown in the same colors on a ribbon representation of a single subunit (b). The main chain electron density for residue Lys136 was unclear; this residue is shown as a dashed line. The subunit structure resembles a ‘leaping dolphin’; TM domains (tail; green), head (pink), dorsal fin (orange), left flipper (yellow) and right flipper (red) are indicated. (c) Sites of subunit–subunit interaction. Two subunits are shown, one (front) in ribbon representation and one (back) in space-filling representation. Panels depict sites of significant interaction; head–body (i), left flipper–dorsal fin (ii), and body–body (iii). The direction of rotation of the structure to obtain the views in panels (ii) and (iii) is indicated with curved arrows. (d) Space-filling representation of the trimer; individual subunits are colored red, blue and green. The putative ATP-binding pocket is indicated, as are the dimensions of the extracellular and TM-domains. Figure partly redrawn from [22], with permission.
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fig1: Representations of the ΔzfP2X4.1 structure. The first P2X receptor structure provides a wealth of new information about the overall fold of the molecule, subunit–subunit interactions, and hints at the location of the ATP binding site. Regions of amino acid sequence (a) contributing to each domain within the ΔzfP2X4.1 crystal structure are shown in the same colors on a ribbon representation of a single subunit (b). The main chain electron density for residue Lys136 was unclear; this residue is shown as a dashed line. The subunit structure resembles a ‘leaping dolphin’; TM domains (tail; green), head (pink), dorsal fin (orange), left flipper (yellow) and right flipper (red) are indicated. (c) Sites of subunit–subunit interaction. Two subunits are shown, one (front) in ribbon representation and one (back) in space-filling representation. Panels depict sites of significant interaction; head–body (i), left flipper–dorsal fin (ii), and body–body (iii). The direction of rotation of the structure to obtain the views in panels (ii) and (iii) is indicated with curved arrows. (d) Space-filling representation of the trimer; individual subunits are colored red, blue and green. The putative ATP-binding pocket is indicated, as are the dimensions of the extracellular and TM-domains. Figure partly redrawn from [22], with permission.

Mentions: Regions of the ΔzfP2X4.1 protein sequence can be related to domains within the crystal structure by imagining the monomer using the analogy of a leaping dolphin [22] (Figure 1a, b). The body of the dolphin is a β-sandwich domain which makes extensive subunit–subunit contacts in the upper regions (Figure 1c); however there are relatively few contacts in the regions proximal to the TM domains. This conformation might allow the TM domains the latitude to move upon agonist binding [22]. When the atoms within the structure are shown in space-filling representation, the dolphin-like monomer subunits are entwined round one another, and cavities between subunits thought to be the ATP binding sites are clearly visible (Figure 1d). There is no immediately obvious pathway for ions through the TM domains, consistent with the expectation that the crystallized protein is in a closed state.


P2X receptors: dawn of the post-structure era.

Young MT - Trends Biochem. Sci. (2009)

Representations of the ΔzfP2X4.1 structure. The first P2X receptor structure provides a wealth of new information about the overall fold of the molecule, subunit–subunit interactions, and hints at the location of the ATP binding site. Regions of amino acid sequence (a) contributing to each domain within the ΔzfP2X4.1 crystal structure are shown in the same colors on a ribbon representation of a single subunit (b). The main chain electron density for residue Lys136 was unclear; this residue is shown as a dashed line. The subunit structure resembles a ‘leaping dolphin’; TM domains (tail; green), head (pink), dorsal fin (orange), left flipper (yellow) and right flipper (red) are indicated. (c) Sites of subunit–subunit interaction. Two subunits are shown, one (front) in ribbon representation and one (back) in space-filling representation. Panels depict sites of significant interaction; head–body (i), left flipper–dorsal fin (ii), and body–body (iii). The direction of rotation of the structure to obtain the views in panels (ii) and (iii) is indicated with curved arrows. (d) Space-filling representation of the trimer; individual subunits are colored red, blue and green. The putative ATP-binding pocket is indicated, as are the dimensions of the extracellular and TM-domains. Figure partly redrawn from [22], with permission.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2824114&req=5

fig1: Representations of the ΔzfP2X4.1 structure. The first P2X receptor structure provides a wealth of new information about the overall fold of the molecule, subunit–subunit interactions, and hints at the location of the ATP binding site. Regions of amino acid sequence (a) contributing to each domain within the ΔzfP2X4.1 crystal structure are shown in the same colors on a ribbon representation of a single subunit (b). The main chain electron density for residue Lys136 was unclear; this residue is shown as a dashed line. The subunit structure resembles a ‘leaping dolphin’; TM domains (tail; green), head (pink), dorsal fin (orange), left flipper (yellow) and right flipper (red) are indicated. (c) Sites of subunit–subunit interaction. Two subunits are shown, one (front) in ribbon representation and one (back) in space-filling representation. Panels depict sites of significant interaction; head–body (i), left flipper–dorsal fin (ii), and body–body (iii). The direction of rotation of the structure to obtain the views in panels (ii) and (iii) is indicated with curved arrows. (d) Space-filling representation of the trimer; individual subunits are colored red, blue and green. The putative ATP-binding pocket is indicated, as are the dimensions of the extracellular and TM-domains. Figure partly redrawn from [22], with permission.
Mentions: Regions of the ΔzfP2X4.1 protein sequence can be related to domains within the crystal structure by imagining the monomer using the analogy of a leaping dolphin [22] (Figure 1a, b). The body of the dolphin is a β-sandwich domain which makes extensive subunit–subunit contacts in the upper regions (Figure 1c); however there are relatively few contacts in the regions proximal to the TM domains. This conformation might allow the TM domains the latitude to move upon agonist binding [22]. When the atoms within the structure are shown in space-filling representation, the dolphin-like monomer subunits are entwined round one another, and cavities between subunits thought to be the ATP binding sites are clearly visible (Figure 1d). There is no immediately obvious pathway for ions through the TM domains, consistent with the expectation that the crystallized protein is in a closed state.

Bottom Line: P2X receptors are non-selective cation channels gated by extracellular ATP.The recent report of the three-dimensional (3D) crystal structure of zebrafish P2X4.1 represents a step change in our understanding of these membrane ion channels, where previously only low-resolution structural data and inferences from indirect structure-function studies were available.The purpose of this review is to place previous work within the context of the new 3D structure, and to summarize the key questions and challenges which await P2X researchers as we move into the post-structure era.

View Article: PubMed Central - PubMed

Affiliation: School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, United Kingdom. YoungMT@cardiff.ac.uk

Show MeSH
Related in: MedlinePlus