PDBsum entry 7bvq

Membrane protein

PDB id: 7bvq

Contents

Protein chains

455 a.a.

Ligands

GLC-GLC

CLR

CAU ×2

SO4 ×8

1WV ×2

CIT ×2

PG4 ×4

Metals

_NA

Waters ×121

References listed in PDB file

Key reference

• Title: Binding pathway determines norepinephrine selectivity for the human β₁ar over β₂ar.
• Authors: X.Xu, J.Kaindl, M.J.Clark, H.Hübner, K.Hirata, R.K.Sunahara, P.Gmeiner, B.K.Kobilka, X.Liu.
• Ref.: Cell Res, 2021, 31, 569-579. [DOI no: 10.1038/s41422-020-00424-2]
• PubMed id: 33093660

Abstract

Beta adrenergic receptors (βARs) mediate physiologic responses to the catecholamines epinephrine and norepinephrine released by the sympathetic nervous system. While the hormone epinephrine binds β₁AR and β₂AR with similar affinity, the smaller neurotransmitter norepinephrine is approximately tenfold selective for the β₁AR. To understand the structural basis for this physiologically important selectivity, we solved the crystal structures of the human β₁AR bound to an antagonist carazolol and different agonists including norepinephrine, epinephrine and BI-167107. Structural comparison revealed that the catecholamine-binding pockets are identical between β₁AR and β₂AR, but the extracellular vestibules have different shapes and electrostatic properties. Metadynamics simulations and mutagenesis studies revealed that these differences influence the path norepinephrine takes to the orthosteric pocket and contribute to the different association rates and thus different affinities.