GPCR Structure: Research Reveals Molecular Origins of Function for a Key Drug Target

Image of β2 adrenoceptor (PDB: 2rh1​) shown binding carazolol (yellow), an inverse agonist, on its extracellular site.
Through an international collaboration, scientists at St. Jude Children’s Research Hospital leveraged data science, pharmacology, and structural information to conduct an atomic-level investigation into how each amino acid in the receptor that binds adrenaline contributes to receptor activity in the presence of this natural ligand. The researchers discovered precisely which amino acids control the key pharmacological properties of the ligand. The adrenaline receptor studied is a member of the G protein-coupled receptor (GPCR) family, and this family is the target of one-third of all Food and Drug Administration (FDA)-approved drugs. Thus, understanding how GPCRs respond to natural or therapeutic ligands is critical for developing new therapies with precise effects on receptor activity. The work was published December 21, 2023 in Science. The article is titled “Molecular Determinants of Ligand Efficacy and Potency in GPCR Signaling.”
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