7XK9

Structure of human beta2 adrenergic receptor bound to constrained isoproterenol

Summary for 7XK9

• Entry DOI: 10.2210/pdb7xk9/pdb
• Descriptor: Endolysin,Beta-2 adrenergic receptor, Camelid Antibody Fragment, (5R,6R)-6-(propan-2-ylamino)-5,6,7,8-tetrahydronaphthalene-1,2,5-triol, ... (4 entities in total)
• Functional Keywords: gpcr, membrane protein
• Biological source: Enterobacteria phage T4 (Bacteriophage T4); More
• Total number of polymer chains: 2
• Total formula weight: 66680.70

Authors

Xu, X.,Shonberg, J.,Kaindl, J.,Clark, M.,Stobel, A.,Maul, L.,Mayer, D.,Hubner, H.,Venkatakrishnan, A.,Dror, R.,Kobilka, B.K.,Sunahara, R.,Liu, X.,Gmeiner, P. (deposition date: 2022-04-19, release date: 2023-04-26, Last modification date: 2023-11-29)

Primary citation

Xu, X.,Shonberg, J.,Kaindl, J.,Clark, M.J.,Stossel, A.,Maul, L.,Mayer, D.,Hubner, H.,Hirata, K.,Venkatakrishnan, A.J.,Dror, R.O.,Kobilka, B.K.,Sunahara, R.K.,Liu, X.,Gmeiner, P.
Constrained catecholamines gain beta 2 AR selectivity through allosteric effects on pocket dynamics.
Nat Commun, 14:2138-2138, 2023

PubMed Abstract: G protein-coupled receptors (GPCRs) within the same subfamily often share high homology in their orthosteric pocket and therefore pose challenges to drug development. The amino acids that form the orthosteric binding pocket for epinephrine and norepinephrine in the β and β adrenergic receptors (βAR and βAR) are identical. Here, to examine the effect of conformational restriction on ligand binding kinetics, we synthesized a constrained form of epinephrine. Surprisingly, the constrained epinephrine exhibits over 100-fold selectivity for the βAR over the βAR. We provide evidence that the selectivity may be due to reduced ligand flexibility that enhances the association rate for the βAR, as well as a less stable binding pocket for constrained epinephrine in the βAR. The differences in the amino acid sequence of the extracellular vestibule of the βAR allosterically alter the shape and stability of the binding pocket, resulting in a marked difference in affinity compared to the βAR. These studies suggest that for receptors containing identical binding pocket residues, the binding selectivity may be influenced in an allosteric manner by surrounding residues, like those of the extracellular loops (ECLs) that form the vestibule. Exploiting these allosteric influences may facilitate the development of more subtype-selective ligands for GPCRs.

PubMed: 37059717
DOI: 10.1038/s41467-023-37808-y

Experimental method

X-RAY DIFFRACTION (3.4 Å)