The study reports the high-resolution crystal structure of a human β2-adrenergic receptor (β2AR) engineered to include T4 lysozyme (T4L) in place of the third intracellular loop, bound to the partial inverse agonist carazolol at 2.4 Å resolution. This structure provides insights into the binding site accessibility and ligand interactions of a human G protein-coupled receptor (GPCR). The second extracellular loop is held out of the binding cavity by disulfide bridges and a short helical segment, enabling ligand binding. Cholesterol mediates parallel receptor associations in the crystal lattice. Despite similarities in ligand binding positions to those in rhodopsin, structural differences highlight challenges in using rhodopsin as a template for modeling other GPCRs. The study also discusses the overall receptor topology, crystal packing interactions, lipid-mediated receptor association, electrostatic charge distribution, extracellular region, ligand binding site, and structural alignment with rhodopsin. The findings contribute to a better understanding of GPCR architecture and ligand binding mechanisms.The study reports the high-resolution crystal structure of a human β2-adrenergic receptor (β2AR) engineered to include T4 lysozyme (T4L) in place of the third intracellular loop, bound to the partial inverse agonist carazolol at 2.4 Å resolution. This structure provides insights into the binding site accessibility and ligand interactions of a human G protein-coupled receptor (GPCR). The second extracellular loop is held out of the binding cavity by disulfide bridges and a short helical segment, enabling ligand binding. Cholesterol mediates parallel receptor associations in the crystal lattice. Despite similarities in ligand binding positions to those in rhodopsin, structural differences highlight challenges in using rhodopsin as a template for modeling other GPCRs. The study also discusses the overall receptor topology, crystal packing interactions, lipid-mediated receptor association, electrostatic charge distribution, extracellular region, ligand binding site, and structural alignment with rhodopsin. The findings contribute to a better understanding of GPCR architecture and ligand binding mechanisms.