Modelling of Adenosine A2a Receptor
This is the PDB3D
Java applet of Scott Legrand.
Use the mouse button(s) for rotation and zoom control.
It's a nice gimmick, but there is a long way to go before the applets can compete with the programs mentioned below.
This model can also be view in the old-fashioned way. 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 a quick overview, you could use the snapshots below (just click on the images to expand them).
First, a fly-by shot of the A2A adenosine receptor from the exofacial or luminal side. In the initial study, mutations in helices 5, 6 and 7 were focused. 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, please refer to
Next, 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.
A detailed view of the adenosine-N6 binding region.
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, the hydrophilic ribose moiety is found
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, the involvement of helix 3 in the binding of agonists
and antagonists is investigated. 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:
