Structure of P2X receptors

Abstract

P2X receptors are trimeric ion channels that open in response to extracellular ATP. The publication of the first X‐ray structure of a closed P2X receptor has confirmed many of the functional experiments carried out since the mid‐1990s and provides a point of reference for the molecular dissection of P2X receptor function. These co‐ordinates shed light on the ATP binding sites housed in the extracellular domain, the contacts between subunits, the pathways for ion access, and the cation‐selective pore that spans the cell membrane. They also provide a template for structure‐based design of much needed pharmacological agents to act on a receptor superfamily whose physiological roles extend from synaptic transmission to inflammation and control of programmed cell death. Interpretation of functional data in the context of this closed P2X receptor structure reveals structural rearrangements in the transmembrane pore and extracellular domain. Here the current understanding of the molecular structure of P2X receptors is reviewed. This review will be of relevance to those interested in the mechanisms that underlie the molecular operation of P2X receptors, and other ion channels gated by diffusible ligands (pentameric Cys‐loop receptors, tetrameric glutamate receptors), as well as trimeric ion channels that are distantly related to P2X receptors (acid‐sensing ion channels and the epithelial sodium channel). WIREs Membr Transp Signal 2012, 1:56–69. doi: 10.1002/wmts.24For further resources related to this article, please visit the WIREs website.

ATP Binding and Channel Activation in P2X Receptors

“…ATP that is positioned at the subunit interfaces adopts an U-shaped conformation [11] . 1) Negatively charged α, β, and γ phosphates groups form salt bridges with the side-chain positively charged nitrogen of K70 (strictly conserved, lower body of subunit A, contacts with the α, β, and γ-phosphate, K67 in rP2X4R, Figure 1), K72 (strictly conserved, lower body of subunit A, contacts with the γ-phosphate, K69 in rP2X4R), N296 (strictly conserved, upper body of subunit B, contacts with β-phosphate, N293 in rP2X4R), R298 (strictly conserved, upper body of subunit B, contacts with the γ-phosphate, R295 in rP2X4R), and K316 (strictly conserved, upper body of subunit B, contacts with the β-and γ-phosphate, K313 in rP2X4R), consistent with previous studies that anticipated a direct involvement of these residues in agonist binding [21] . These ionic interactions with β-and γ-phosphate groups may provide an explanation why P2X receptors preferentially accommodate ATP over ADP and AMP [22] ;…”

Agonist Antagonist Interactions at the Rapidly Desensitizing P2X3 Receptor

“…Knowledge on the AA composition of the agonist binding pouch of P2XRs was derived for many years from mutagenesis studies [6,29]. The crystallization of the zebrafish P2X4R at first in its closed and then in its ATP-complexed (possibly open) state gave a major thrive to these investigations [27,30]. Whereas originally only the AA residues with significance for agonist binding were studied for these receptors, more recently also AAs involved in antagonist binding have been increasingly investigated [30].…”

“…The crystallization of the zebrafish P2X4R at first in its closed and then in its ATP-complexed (possibly open) state gave a major thrive to these investigations [27,30]. Whereas originally only the AA residues with significance for agonist binding were studied for these receptors, more recently also AAs involved in antagonist binding have been increasingly investigated [30]. The chimera replacing the region between the third and fourth conserved cysteine residues of the P2X1R with the corresponding part of P2X2 reduced NF449 sensitivity a thousand fold at the P2X1-2R-chimera to that of the P2X1R [31].…”

Omnipresent purinergic signaling: an editorial essay

“…There is much current interest in the pathophysiology of purinergic signaling and its therapeutic potential for the treatment of pain, bladder incontinence, osteoporosis, cystic fibrosis, diseases of the CNS, and cancer 19. All these aspects of purinergic signaling will be extensively discussed in a series of papers appearing on the pages of WIRES Membrane Transport and Signaling , some of which have already been published,20,21 or are in press,2,22,23,24 and more will appear in the near future.…”