Friday, March 24, 2017

Signaling inside out

G protein-coupled receptors are a very large superfamily of transmembrane proteins that transmit signals into cells. They all have seven membrane-spanning helices, and most of them can activate a so-called G-protein that binds guanine nucleotides. I say “most” because there are some families that are sometimes grouped with GPCRs that seem to signal independently of G-proteins, for instance the Hedgehog receptor Smoothened and the PAQR receptors that are the subject of this post.

The early and mid-2000s saw the first structures of these receptors, at first in the “off” state with antagonists bound, and later in the “on” state with agonists bound. I have posted about some of these structures before. These structures revealed that when an agonist binds to the outside of the receptor, the outer halves of several of the helices in the bundle move slightly closer together, and this triggers, in a kind of “see-saw” manner, their outer halves to splay apart, creating the G-protein binding site. In particular, the outside ends of TM5(blue-green), TM7(red-orange), and to a lesser extent TM6 (light orange) move in, and the outer end of TM6 moves dramatically out, with TM5 and TM8 moving less. Here, the inactive "off" state is in rainbow colors, and the active "on" state is in light blue, and this figure is based on two structures of the beta2 adrenoceptor ((1) and (2)).