Membrane protein structures--part 3

I haven't posted here for a long time, so I decided to summarize a little of membrane structural biology over the last few months.

By far the most exciting advancements have occurred in the field of GPCRs. The Stevens group at The Scripps Research Institute (who also published the adrenoceptor structure mentioned a few posts ago) published a new structure of the same receptor, but with a different antagonist (3D4S). In this structure, a cholesterol molecule was observed in a slightly different location from in the previous one, which led to the discovery of a putative cholesterol recognition motif. Also, Schertler and colleagues at the MRC laboratory in Cambridge solved the structure of the turkey beta1 adrenoceptor with yet a third antagonist (2VT4).


One might think that with the first structures of "real" pharmacologically relevant GPCRs being solved, the relevance of rhodopsin, the previously prototypical member of the superfamily, might be on the way out. However, this is most definitely not a conclusion to jump to automatically, as a recent structure (3CAP) from Park et. al. demonstrates. This is the structure of opsin, which is rhodopsin without the covalently attached light-absorbing molecule retinal. Many of the helices show a change in conformation relative to rhodopsin, and based on some biochemical data showing constitutive activity in opsin, the authors propose that this structure may represent the long-sought active state of the receptor. This structure shows changes of a significantly greater magnitude from dark state rhodopsin than any other structure previously proposed to be activated, and this makes me more inclined to believe that it could actually be active. In fact, I am guessing the shift observed in opsin may be TOO large to represent normal activation, and may represent a partial unfolding of the receptor due to complete loss of the stabilizing effect of retinal. Though much less notable, for the sake of completeness I will add that a structure of squid rhodopsin has also been published (2Z73).

As for ion channels, a bacterial homologue of the Cys-loop superfamily, to which nicotinic and GABA(A) receptors in animals belong, has been solved (2VL0). The ligand of this receptor is unknown, and the low homology with other Cys-loop receptors along with the mediocre resolution mean that this structure will most likely not be useful for modeling studies. Also, this is not recent, but the structure of the acid-sensing channel ASIC1 (2QTS) provides insight into a new fold of ion channel. The most intriguing property of this structure is the fact that the homotrimeric channels show each monomer to be in a different conformation, with some of the differences being large (almost 10 Angstroms). This may be an artifact of the crystal structure, but if not, this would be an unprecedented finding.

In the area of transporters, not that much has happened, although there is a structure of a sodium-galactose transporter by a group at UCLA due to be released soon. Intriguingly, this transporter is related to LeuT, despite a lack of sequence similarity aside from conservation of a few glycines at proposed hinge regions. The fact that this transporter is in the inward-facing conformation, as opposed to LeuT, which was in the outward-facing conformation, should provide insight into the transport mechanism.