Adenosine Receptors

The pharmacology and selective ligands for these receptors are described on a separate page.

This page is a digest of previous and current work on the human A_2A adenosine receptor in our lab. To find out more about the origin of the work presented here, please have a look at:

• Kim, J.; Wess, J.; van Rhee, A.M.; Schöneberg, T.; Jacobson, K.A.
  Site-directed mutagenesis identifies residues involved in ligand recognition in the human A_2a adenosine receptor. J. Biol. Chem., 1995, 270:13987-13997.
  

You might want to check out the Introduction to Modelling G Protein-Coupled Receptors before reading on.

If your browser is configured to use, e.g., RasMol or XMol to display molecules in the PDB-format (through chemical MIME), all you need to do is follow this link for the coordinates.

For a quick overview, you could use the snapshots below (just click on the images to expand them). We hope you'll enjoy them as much as we do.

First, a fly-by shot of the A_2A adenosine receptor from the exofacial or luminal side. In our initial study, we focussed on mutations in helices 5, 6 and 7. The non-selective adenosine receptor agonist NECA (N-ethyl-5'-carbamoyladenosine; shown in red) was docked into the central cavity of the helical bundle. Residues that, when mutated to alanine, affect ligand binding are indicated in light green, and residues investigated, but found unimportant for ligand binding are indicated in yellow. For a detailed analysis of the study we refer you to our paper cited above.

Next, we have a snapshot of the adenosine binding site from the inside of the helical bundle, looking at helices 5, 6, and 7. Note the distribution of important residues around the centrally-placed ligand.

For a detailed view of the adenosine-N⁶ binding region, we supply this one:

Mutation of N253 to either A, S, or Q was detrimental to binding of both agonists and antagonists. M270 is supposedly responsible for differences in pharmacology between species.

Apparently, the adenine moiety of adenosine prefers a hydrophobic domain in the receptor.

On the opposite side of the molecule we find the hydrophilic ribose moiety in a hydrophilic domain of the binding pocket. The mutant receptor S277A no longer binds adenosine derivatives with high affinity, but xanthine binding is normal.

Mutation of some residues leads to considerable effects on ligand binding capacity, without those residues being directly involved in ligand binding. Such residues may be found in an interhelical contact region.

In a follow-up study, we investigated the involvement of helix 3 in the binding of agonists and antagonists. A detailed picture of the area of interest is provided here:

For some years, there has been a discussion going on about the mode of binding of xanthine-derived antagonists to adenosine receptors. There are three dominant models:

• 1. the "all nitrogen" model, which maps nitrogen atoms present in xanthines unto the equivalent nitrogen atoms in the adenine moiety of adenosine,

• 2. the "flipped" model, which rotates the xanthine by 180 degrees around its longitudinal axis relative to the "all nitrogen" model, and
  

  

• 3. the "N⁶/C8" model, which maps the C8-region of xanthines onto the N⁶-region of adenosine.
  

These models were developed by analysis of Structure-Affinity Relationships for both agonists and antagonists. They have been discussed extensively by:

• van Galen, P.J.M.; van Vlijmen, H.W.T.; IJzerman, A.P.; Soudijn, W.
  A Model for the Antagonist Binding Site on the Adenosine A₁ Receptor, Based on Steric, Electrostatic, and Hydrophobic Properties.
  J. Med. Chem., 1990, 33: 1708-1713.
  
• van der Wenden, E.M.; Price, S.L.; Apaya, P.R.; IJzerman, A.P.; Soudijn, W.
  Relative Binding Orientations of Adenosine-A₁ Receptor Ligands - A Test-Case for Distributed Multipole Analysis in Medicinal Chemistry.
  J. Computer-Aided Mol. Design, 1995, 9: 44-54.
  

Our work in Molecular Biology and Computational Chemistry led us to this preferred model, but the discussion is still very much alive.