January 31, 2012
Congratulations to the publication of the first GPCR structure in 2012! These congrats go to the Kobilka, Haga and Kobayashi teams that reported the X-ray crystallographic structure of the M2 muscarinic acetylcholine receptor this weeks' issue of Nature. The bound antagonist (3-quinuclidinyl-benzilate) is bound in the center of a long aqueous tubular structure that has not seen before in any GPCR. Apart from the common arrangement of the 7 TMs, the comparison of the shape of the M2 binding pockets with those of other receptors (b2, A2A, CXCR4, D3 and H1 receptor) shows that the binding modes are very different from each other (as compared to b2, A2A, CXCR4, D3 and H1 receptors, see Fig.4 here). The ligand binding pocket is really a channel that goes two thirds through the membrane, and opening up the remainder would likely convert this GPCR into a water pore. Turns out that the M2 binding pocket is very similar amongst the family of muscarinic acetylcholine receptors, explaining the difficulty of developing specific ligands.
As seen with many other GPCR structures, T4 lysozyme inserting into the third intracellular loop provides for strong packing interactions between layers in the M2-T4L crystal. No surprise here. As of writing this, the coordinates are not yet available (access code 3UON) but should be released soon.
PS: More GPCR structures to come: e.g. the yet unpublished S1P1 and k-opioid receptor structure are advertised here