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Comment
. 2019 Jan 22;58(3):137-139.
doi: 10.1021/acs.biochem.8b01237. Epub 2018 Dec 31.

Structural Basis of Partial Agonism at the β2-Adrenergic Receptor

Arun K Shukla  1
Affiliations
Comment

Structural Basis of Partial Agonism at the β2-Adrenergic Receptor

Arun K Shukla. Biochemistry. .
No abstract available

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Conflict of interest statement

Notes

The author declares no competing financial interest.

Figures

Figure 1
Figure 1. Overall crystal structure of the salmeterol-bound β2-adrenergic receptor (β2AR).
(A) Cartoon representation of the crystal strucuture of the human β2AR in complex with salmeterol stabilized by a nanobody, termed Nb71. The N-terminal T4 lysozyme is colored orange, β2AR blue, Nb71 gray, and salmeterol red. The image is generated from the Protein Data Bank (PDB) coordinates of the salmeterol-bound β2AR (PDB entry 6MXT) using Pymol. (B) Chemical structures of the native β2AR agonist epinephrine (also termed adrenaline) and salmeterol and comparison of their modes of binding to the β2AR. The “exosite” occupied by the aryloxyalkyl tail of salmeterol is indicated. The binding mode of epinephrine is derived from a previously determined crystal structure of β2AR in complex with epinephrine (PDB entry 4LDO).
Figure 2
Figure 2. Key structural differences between the binding of epinephrine and salmeterol.
(A) Interaction of epinephrine and (B) salmeterol in the orthosteric binding pocket of the β2AR derived from their respective crystal structures. A key difference in the salmeterol-bound structure is the lack of a hydrogen bond between the ligand and Asn2936.55 that leads to a disrupted polar network involving Ser2045.43, Asn2936.55, and the ligand.
Figure 3
Figure 3. Outward movement of TM6 in various active β2AR structures.
(A) Superimposition of the crystal structures of carazolol, salmeterol, and epinephrine-bound β2AR reveals a somewhat intermediate outward movement of TM6 (approximately 8 Å) in the salmeterol-bound structure compared to the epinephrine-bound structure (approximately 11 Å). (B) Similarly, the outward movement of TM6 in salmeterol-bound β2AR is significantly smaller than that in the fully active receptor conformation in the β2AR–Gαs complex (~13 Å). The images are generated using PyMol on the basis of previously determined crystal structures (2RH1 for carazolol-bound β2AR and 3SN6 for the β2AR–Gαs complex). The side chain of Glu296 present at the far cytoplasmic end of TM6 is highlighted.
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