IUPHAR DATABASE | HOT TOPICS

Hot Topics

The following are recent publications of interest.

Revised recommendations for nomenclature of ligand-gated ion channels

The nomenclature of ligand-gated ion channels and their subunits has recently been re-examined by NC-IUPHAR. Their revised recommendations for nomenclature are summarised here.

Crystal Structure of a human A_2A Adenosine Receptor

Comments by S.P.H. Alexander, T.I. Bonner and A. Christopoulos:
Following on from reports of β-adrenoceptor structures reported recently, the 2.6 Å crystal structure of a further Gs-coupled receptor has been reported. The A_2A receptor was modified, replacing the third intracellular loop with T4 bacteriophage lysozyme and deleting the C-terminus after the initial 25-30 residues beyond TM7. Purification in the presence of theophylline, which was later exchanged for the more selective A_2A receptor antagonist ZM241385 allowed diffraction data to be obtained from the best 13 crystals. From the resulting solved structure, there were three main findings of particular note. The first is the presence of 4 disulfide bonds in the extracellular loop regions, which yields an organization that is very different from previously solved structures of rhodopsin and the β-adrenoceptor structures. Second, the transmembrane helices diverge from the orientations adopted by the corresponding domains in the rhodopsin and adrenoceptor structures. Finally, and perhaps most strikingly, these structural features result in a binding mode of the antagonist that places it in an extended conformation, almost perpendicular to the plane of the membrane, lined up against TM7 and interacting with the loop regions. This pose is very different to that predicted previously based on homology models.

(1) Jaakola VP, Griffith MT, Hanson MA, Cherezov V, Chien EY, Lane JR, Ijzerman AP, Stevens RC. (2008)
The 2.6 Angstrom Crystal Structure of a Human A_2A Adenosine Receptor Bound to an Antagonist. Science. Nov 21; 322 (5905): 1211-7. [PMID: 18832607]

Structure of the β₁-adrenergic receptor

Comments by A.J. Harmar:
Schertler and colleagues report the crystal structure of a β₁-adrenergic receptor in complex with the antagonist cyanopindolol. Site directed mutagenesis was used to improve the thermostability of the protein and lock it in the antagonist state. This approach may be a fruitful one for determining the structures of other GPCRs.

(1) Warne T, Serrano-Vega MJ , Baker JG, Moukhametzianov R, Edwards PC, Henderson R, Leslie AGW, Tate CG, Schertler GFX. (2008)
Structure of a beta1-adrenergic G-protein-coupled receptor. Nature. Jul 24; 454 (7203): 486-91 [PMID: 18594507]

Crystal structure of human β₂-adrenergic receptor

Comments by A.P.Davenport:
To date, only 148 unique structures for membrane proteins have been determined, only 4 of these are human in origin and only one crystal structure of a GPCR has been solved, the visual sensory protein rhodopsin. Three papers in Science and Nature now report the structure of the human β₂-adrenergic receptor.

(1) Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK. (2007)
Crystal structure of the human beta2 adrenergic G-protein-coupled receptor. Nature. Nov 15; 450 (7168): 383-7. [PMID: 17952055]

(2) Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC. (2007)
High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science. Nov 23; 318 (5854): 1258-65. [PMID: 17962520]

(3) Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK. (2007)
GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function. Science. Nov 23; 318 (5854): 1266-73. [PMID: 17962519]