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)).
