Receptor Structure
GPCRs are integral membrane proteins that possess seven membrane-spanning domains or transmembrane helices. The extracellular parts of the receptor can be glycosylated. These extracellular loops also contain two highly-conserved cysteine residues that form disulfide bonds to stabilize the receptor structure. Some seven-transmembrane helix proteins (channelrhodopsin) that resemble GPCRs may contain ion channels, within their protein.
Similar to GPCRs, the adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2) also possess 7 transmembrane domains. However ADIPOR1 and ADIPOR2 are orientated oppositely to GPCRs in the membrane (i.e., cytoplasmic N-terminus, extracellular C-terminus) and do not associate with G proteins.
Early structural models for GPCRs were based on their weak analogy to bacteriorhodopsin, for which a structure had been determined by both electron diffraction (PDB 2BRD, 1AT9) and X ray-based crystallography (1AP9). In 2000, the first crystal structure of a mammalian GPCR, that of bovine rhodopsin (1F88), was solved. While the main feature, the seven transmembrane helices, is conserved, the relative orientation of the helices differ significantly from that of bacteriorhodopsin. In 2007, the first structure of a human GPCR was solved (2R4R, 2R4S). This was followed immediately by a higher resolution structure of the same receptor (2RH1). This human β2-adrenergic receptor GPCR structure, proved highly similar to the bovine rhodopsin in terms of the relative orientation of the seven-transmembrane helices. However the conformation of the second extracellular loop is entirely different between the two structures. Since this loop constitutes the "lid" that covers the top of the ligand binding site, this conformational difference highlights the difficulties in constructing homology models of other GPCRs based only on the rhodopsin structure.
The structures of activated and/or agonist-bound GPCRs have also been determined. These structures indicate how ligand binding at the extracellular side of a receptor leads to conformational changes in the cytoplasmic side of the receptor. The biggest change is an outward movement of the cytoplasmic part of the 5th and 6th transmembrane helix (TM5 and TM6). The structure of activated beta-2 adrenergic receptor in complex with Gs confirmed that the Gα binds to a cavity created by this movement.
Read more about this topic: G Protein-coupled Receptor
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