Molecular Recognition Section, Division of Intramural Research : NIDDK : National Institutes of Health

P2 Purinoceptors

The information on this page was excerpted from:

  • van Rhee, A.M.; Fischer, B.; Jacobson, K.A.
    Modelling the P2Y purinoceptor using rhodopsin as template.
    Drug Design & Discovery, 1995, 13: 133-154.

for a complete report, and more details, please use this publication as a reference.

General Introduction
The P2Y1 purinoceptor cloned from chick brain (Webb, T. et al (1993) FEBS Lett., 324, 219-225) is a 362 amino acid, 41 kDa protein. To locate residues tentatively involved in ligand recognition a molecular model of the P2Y1 purinoceptor was constructed. The model was based on the primary sequence and structural homology with the G protein-coupled photoreceptor rhodopsin, in analogy to the method proposed by Ballesteros and Weinstein ((1995) Meth. Neurosci. 25, 366-428).

New and Selective Ligands
The complete elucidation of P2 subtypes and mechanisms of action have been impeded by the limited number of stable and selective agonists and antagonists available. We have recently reported the synthesis of a variety of ATP analogues modified at either the ribose or the purine, including a series of functionalized congeners based on the potent P2Y purinoceptor agonist 2-methylthioadenosine 5'-triphosphate (2MeSATP). 14, 15 The 2-thio-ether derivatives were shown to be potent P2Y purinergic ligands stimulating the production of inositol phosphates in turkey erythrocyte membranes with K0.5-values ranging from 1.5 to 770 nM. Moreover, N6-methyl-2-(5-hexenylthio)-ATP was shown to be a potent and selective P2Y agonist (K0.5 = 26 7 nM). Since substitution at the N6 position of the adenine moiety seemed to convey selectivity for a specific P2Y receptor subtype, 14, 15 we now synthesized the 5'-mono- and triphosphates of N6,N6-dimethyl-adenosine and N6-(2-phenylethyl)-adenosine. Progress in the development of antagonists has also been made recently. 16, 17, 18

Sequence Analysis

Dendrogram composed for the sequences of 29 G protein-coupled receptors - including orphan receptors - and bacteriorhodopsin shows that the known metabotropic P2 receptor sequences - P2Y and P2U - are more closely related to each other than to any other receptor

The dendrogram above, composed for the sequences of 29 G protein-coupled receptors (including orphan receptors) and bacteriorhodopsin shows that the known metabotropic P2 receptor sequences (P2Y and P2U) are more closely related to each other than to any other receptor. Comparison of the P2Y (chick) and P2U (rat) receptor subtypes with other GPCR sequences showed only low percentages of sequence identity (e.g., angiotensin II - P2Y 27 %, angiotensin II - P2U 22 %, thrombin - P2Y 25 %, thrombin - P2U 25 %; interleukin 8 - P2Y 22 %; interleukin 8 - P2U 23 %).

The P2 receptors, regardless of subtype, whether GPCR or ligand-gated ion channel, are often regarded as related to the better characterized and more widely known adenosine receptors [Burnstock 4 and most subsequent reviews]. From the dendrogram, however, it must be concluded that, e.g., the A2A adenosine receptor is more closely related to the biogenic amine receptors, than to any of the GPCR P2 receptors. Both P2Y and P2U receptors bear only a marginal sequence identity with the A1 adenosine receptor (21 % for P2Y and less than 12 % for P2U receptor). P2 receptors are more closely related to the PAF, AT1A, and IL-8A receptors, and various orphan receptors, than to any other GPCR subfamily.

A comparison of P2Y vs. P2U receptors revealed 38.8 % identity and 58.6 % similarity. In the transmembrane regions the identity percentage was even higher - 52 %.

Bacteriorhodopsin, included to facilitate comparison with other modelling studies, [e.g., 27, 35] is clearly not related to any of the GPCR subfamilies. The degree of relatedness between bacteriorhodopsin and GPCRs shown in the dendrogram is probably an overestimate of the actual distance, caused by the residue alignment procedure of the program.

Several residues that have been shown to be critical in ligand binding in other GPCRs are conserved in the P2Y1 purinoceptor.

Receptor Model
Potential binding sites for agonists have been explored by docking several derivatives (including newly synthesized N6-derivatives) into the model. The N6-phenylethyl substituent is tolerated pharmacologically, and in our model this substituent occupies a region predominantly defined by aromatic residues such as F51 (TM1), Y100 (TM2) and F120 (TM3). The dimethylated analogue of ATP, N6,N6-dimethyl-adenosine 5'-triphosphate, is less well tolerated pharmacologically, and our model predicts that the attenuated activity is due to interference with hydrogen bonding capacity to Q296 (TM7).

The also model suggests four basic residues (H121 in TM3, H266 and K269 in TM6 and R299 in TM7) near the extracellular surface that might be involved in ligand binding. These basic residues might be essential in coordinating the triphosphate chain of the endogenous ligand adenosine 5'-triphosphate (ATP).

Transmembrane domain 5 thru 7, with ATP bound
Figure 2: Transmembrane domain 5 thru 7, with ATP bound.

Figure 2 is an cut-away drawing of TMs 5-7, shown to contain multiple ligand binding residues in the A2A receptor. 51 The binding of the endogenous ligand ATP seems to occur around the upper third to upper half of the helical bundle. ATP is oriented in the plane of the lipid bilayer, almost perpendicular to the TMs. Figure 2 also demonstrates the use of "membrane anchors" near the bottom of TM5 and TM7, and the top of TM6.

The phosphate binding domain in the P2Y1 purinoceptor
Figure 3A: The phosphate binding domain in the P2Y1 purinoceptor.

Figures 3A and 3B focus on the ligand binding domain (BD) formed by TMs 5-7.

It appears that the binding of the triphosphate moiety is a major determinant in binding of ligands to the P2Y1 purinergic receptor. Since this part of the molecule contains multiple negative charges, one would expect to find counterions in the BD.

Indeed, the P2Y1 receptor sequence contains several positively charged residues. Our modelling study reveals that, of these, Lys269 (TM6) and Arg299 (TM7) are likely candidates for this function and are appropriately positioned within the helical bundle to execute this function.

We propose that these two basic residues are assisted by two histidine residues, His121 (TM3) and His266 (TM6), and one tyrosine residue, Tyr125 (TM3)(Figure 3A). These residues tentatively coordinate the alpha-phosphate (His121 and R299), the beta-phosphate (Y125, K269 and R299), and the gamma-phosphate (His266, and K269).

Although adenosine 5'-monophosphate analogues are widely regarded as inactive at P2 purinergic receptors, 2, 5, 6 Fischer et al 14 recently demonstrated that one monophosphate analogue in particular, 2-(5-hexenyl)thio-adenosine 5'-monophosphate, is a more potent (K0.5 = 328 43 nM; 8.5-fold over ATP) agonist at P2Y receptors on turkey erythrocytes than ATP (K0.5 = 2800 700 nM).

In our model there is sufficient coordination of the alpha-phosphate to warrant such an interaction, although the number of stabilizing interactions, and hence the interaction energy and affinity, will be lower than in the case of the corresponding triphosphate. This is pointedly illustrated by the K0.5 values of 2-(5-hexenylthio)-ATP (10 4 nM) and 2-(5-hexenylthio)-AMP (328 43 nM).14 Since the interaction between the receptor and a ligand monophosphate is much weaker than with a triphosphate, the effect of substituents at distal sites, such as in N6PEAMP (no effect at 10-4 M) and N6diMeAMP (no effect at 10-4 M), increases and the combined effect of deleting two phosphates and adding N6-substituents proved detrimental to activity.

Although not directly involved in ligand binding, Pro218 in TM5 and Pro264 in TM6 have a great impact on receptor structure, and therefore, the BD. They are both located at the same distance from the membrane surface as the ligand and, more importantly, Phe215 and Phe219 (Figure 3A, far right), located at opposite sides of the discontinuity formed by Pro218, are in close proximity of the terminal phosphate of ATP. This particular geometry is highly suggestive of the much heralded, but as yet unproven conformational change mechanism induced by agonists.

The nucleoside binding domain in the P2Y1 purinoceptor
Figure 3B: The nucleoside binding domain in the P2Y1 purinoceptor.

Interestingly, Erb et al 41 showed that Lys289 (TM7) in the mouse P2U receptor, corresponding to Gln296 (TM7)(Figure 3B, top left) in the chick P2Y receptor, when mutated to an arginine, reversed the selectivity of the triphosphates ATP and UTP to the corresponding diphosphates. In our proposed model Gln296 (TM7) is not in the vicinity of the phosphate BD, and this suggests that P2Y and P2U receptors display significantly different modes of binding of ligands, as already implied by the pharmacology-derived nomenclature of the receptors.

Two other residues were tentatively involved in coordinating the ribose moiety. The side chain of Ser303 (TM7)(Figure 3B, left center) and the O2' are separated by only 3.03 Å. The side chain of Ser306 (TM7)(Figure 3B, bottom center) is within hydrogen bonding distance of O2' at 2.95 Å and O3' at 2.84 Å.

Ligand Docking
Ligand docking was initially performed with ATP, using a typical conformation based on crystallographic data for protein-bound nucleotides. To avoid the characteristically curled conformation of the triphosphate chain found in several phosphate transferases (The structure in Figure 4 without explicit hydrogens), we opted to use the nucleotide bound to the phosphate hydrolase transducin (The structure in Figure 4 with explicit hydrogens), 38 even though it involved substituting the purine guanine with the purine adenine.

Comparison of nucleotides bound to phosphate transferases or
phosphate hydrolases
Figure 4A: Comparison of nucleotides bound to phosphate transferases or phosphate hydrolases.
(Alignment of the adenine moieties.)

The effect of the conformation of the triphosphate, becomes even more clear when the triphosphate moieties are aligned (Figure 4B), rather than the adenine moieties (Figure 4A).

Comparison of nucleotides bound to phosphate transferases or
phosphate hydrolases
Figure 4B: Comparison of nucleotides bound to phosphate transferases or phosphate hydrolases.
(Alignment of the triphosphate moieties.)

The orientation of the adenine moiety relative to the ribose ring was anti (i.e., the dihedral angle C9-N9-C1'-O4' was 30.18°). The ring puckering, defined by the dihedral angle C1'-C2'-C3'-C4', was -3.85°, resulting in a 2'-exo, 3'-endo conformation for the two hydroxyl groups.

We have sought to identify positively charged amino acid residues (Arg or Lys) as anchoring points which could contribute major electrostatic interactions with the phosphates of ATP. Such residues should be conserved within the P2 GPCR family and should also be pointing towards the center of the receptor cavity. Likewise, they should probably be located around the middle or upper third of the transmembrane regions, where most of the non-peptide GPCRs are thought to bind ligands. These requirements only yield two possible anchoring points: Lys269 in TM6 and Arg299 in TM7.

In addition, His250 in the A2A receptor 51 and His265 in the NK1 receptor, 50 [the equivalents of His266 (TM6) in the P2Y receptor and His262 in the P2U receptor] were both shown to be important for ligand binding. The same holds true for Arg265 (P2U), Asn253 (A2A) and Phe268 (NK1) [the equivalents of Lys269 (TM6)], Lys289 (P2U) and Tyr271 (A2A) [the equivalents of Gln296 (TM7)], Arg292 (P2U) and Ile274 (A2A) [the equivalents of Arg299 (TM7)], His278 (A2A) corresponding to Ser303 (TM7), and Ser281 (A2A) corresponding to Ser306 (TM7).

In contrast, Lys114 (TM3) in the P2Y and Lys107 (TM3) in the P2U receptor were not implicated in ligand binding 41 , whereas mutation of the equivalent residue, Asp99, in the rat m1 receptor resulted in loss of affinity. 49 This residue is located at the fringe of the transmembrane domain or even in the first extracellular loop in our model. It is therefore likely that the residue is involved in accessibility of the ligand binding domain or in maintaining a specific structure in the loop.

Thus, we identified at least eight residues, Gln296 (TM7) in the adenine binding domain, Ser303 and Ser306 (both TM7) in the ribose binding domain, His121 and Tyr125 (TM3), His266 and Lys269 (TM6), and Arg299 (TM7) in the triphosphate binding domain, that are involved in ligand binding according to this model. Furthermore, we have shown that our model is consistent with the current pharmacological data.


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