17 June 2020
And… we’re live! Our manuscript is out in Nature: ‘Structural basis of the activation of a metabotropic GABA receptor’. A ‘movie’ of four GABA(B) heterodimer cryoEM structures along its activation pathway.
After our first unsuccessful attempts in 2017, Hamidreza Shaye (Cherezov lab) managed to purify a superb heterodimer sample. With that, we started with an agonist-bound state, which showed a mixture of (at least) two conformations (‘int-1’ and ‘int-2’).
In addition, we solved the ‘apo’ structure and the ‘active’ agonist/PAM bound state. This allowed us to assemble most of GABA(B)’s activation pathway, starting with the agonist in the GB1 ECD (blue), propagating through to the intracellular side of the GB2 TMDs (yellow).
Another exciting finding was the unexpected binding site of the PAM. We found a strong density at the dimer interface, which we confirmed by mutational studies (IP1 assays). It shows that PAMs can act like a glue, bridging the two subunits in the active conformation.
This was yet another fantastic collaboration with the Cherezov and Katritch labs and includes beautiful biochemistry from our colleagues in Montpellier around the one and only Jean-Philippe Pin.