February 18, 2012
New and Different GPCR Binding Pockets
What a staggering variety of access to GPCR binding pockets there is. The recently published GPCR structures shed new light on the exquisite architecture of GPCR binding pockets:
1. An internal hydrophobic binding pocket that is pretty much closed towards the aqueous phase was identified in the crystal structure of the sphingosine 1-phosphate receptor 1 (S1P1-T4L) with a bound sphingolipid mimic (antagonist). Similar to rhodopsin, the ligand can access to the deep binding cavity from the hydrophobic section of the membrane.
Crystal Structure of a Lipid G Protein–Coupled Receptor
Michael A. Hanson, Christopher B. Roth, Euijung Jo,Mark T. Griffith, Fiona L. Scott, Greg Reinhart, Hans Desale, Bryan Clemons, Stuart M. Cahalan, Stephan C. Schuerer, M. Germana Sanna, Gye Won Han, Peter Kuhn, Hugh Rosen, Raymond C. Stevens
Science Vol. 335 no. 6070 pp. 851-855; 2012
2. In addition to this conventional ligand binding location, there seems to be a site close to the intracellular surface of GPCRs that serves as an alternate way to modulate GPCR activity in A2A adrenergic receptor and unrelated GPCRs. The structure of the A2A adenosine receptor with a Fab fragment (Fab2839) reveals how it penetrates the receptor with its CDR-H3 domain. The crux is that the interaction is similar to that of the activated b2-adrenergic receptor and that of opsin with a bound peptide; interestingly, the binding of the Fab fragment inactivates the A2A adenosine receptor. This discovery could have huge ramifications, since it offers an alternate way to modulate GPCR activity, without occupying the standard central ligand binding pocket.
Hino, T., Arakawa, T., Iwanari, H., Yurugi-Kobayashi, T., Ikeda-Suno, C., Nakada-Nakura, Y., Kusano-Arai, O., Weyand, S., Shimamura, T., Nomura, N., Cameron, A., Kobayashi, T., Hamakubo, T., Iwata, S., & Murata, T. (2012). G-protein-coupled receptor inactivation by an allosteric inverse-agonist antibody Nature DOI:10.1038/nature10750
All this news is phantastic! The more we look the more we see.
Cheers,
Peter