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β2-Adrenergic Receptor Structures
Valda Vinson and Nancy Gough (27 November 2007)
Sci. STKE 2007 (414), tw434-tw434. [DOI: 10.1126/stke.4142007tw434]
Abstract »  
Posted E-Letters:

The Trouble with Going from Structure to Function

To infer receptor function from crystal structures is very difficult, because the conditions for crystallization are far from those conditions necessary for in vivo function. The recent deposition of the coordinates and structure factors for a chimera of the β2 adrenergic receptor (β2AR) and T4 lysozyme (β2AR-T4L) in the Protein Data Bank 2RH1, allows for some further observations that were not reported in the original paper.

The 2RH1 structure shows that the carazolol ligand lies within 8 to 10 Angstroms of cysteine, C106 (also called C3.25 or CysIII:01), which is usually considered to be in a disulfide bond. The binding of carazolol is sufficiently close that should the cysteine exist in a reduced state, then the acid to base change of this or the other surrounding cysteines, or both, would be expected to modulate ligand binding. A two-state model suggesting that cysteine modulation accounts for many of the experimentally observed redox- and pH-dependent activation properties of the β2AR has been proposed (see Rubenstein et al. 2006). This model also allows for an electrostatic selection of the ligand for the acid or base state of the receptor. In this model, carazolol, a partial inverse agonist, would favor the acid over the base state.

Although the detailed study of β2AR structure is important, the overall changes that lead to receptor activation need a more inclusive activation model. Toward this goal, cysteine modulation of ligand binding appears to accommodate many of the experimental findings concerning receptor activation (see Rubenstein and Lanzara, 1998; Rubenstein et al. 2006). One of the conceptual difficulties with this model has been the persistent belief that the essential C106 exists only as part of a disulfide bond. This has been partly due to the published crystal structures of rhodopsin (1F88) and now the β2AR (2RH1) that show a disulfide bond with this conserved cysteine. The fact that in vivo reducing conditions would likely lead to a reduction of this disulfide bond, and thereby an increase in the functional receptor response, needs more serious consideration by the scientific community in order to advance our understanding of how these receptors function.


L. A. Rubenstein, R. J. Zauhar, R. G. Lanzara, Molecular dynamics of a biophysical model for β2-adrenergic and G perotein-coupled receptor activation. J. Mol. Graph. Model 25, 396-409 (2006). [Abstract] [Full Text]

L. A. Rubenstein, R. G. Lanzara, Activation of G protein-coupled receptors entails cysteine modulation of agonist binding. J. Mol. Structure (Theochem) 430, 57-71 (1998). [Full Text]

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