Structure-inspired design of β-arrestin-biased ligands for aminergic GPCRs. Nat Chem Biol 2018 Feb;14(2):126-134
Date
12/12/2017Pubmed ID
29227473Pubmed Central ID
PMC5771956DOI
10.1038/nchembio.2527Scopus ID
2-s2.0-85040926100 (requires institutional sign-in at Scopus site) 149 CitationsAbstract
Development of biased ligands targeting G protein-coupled receptors (GPCRs) is a promising approach for current drug discovery. Although structure-based drug design of biased agonists remains challenging even with an abundance of GPCR crystal structures, we present an approach for translating GPCR structural data into β-arrestin-biased ligands for aminergic GPCRs. We identified specific amino acid-ligand contacts at transmembrane helix 5 (TM5) and extracellular loop 2 (EL2) responsible for Gi/o and β-arrestin signaling, respectively, and targeted those residues to develop biased ligands. For these ligands, we found that bias is conserved at other aminergic GPCRs that retain similar residues at TM5 and EL2. Our approach provides a template for generating arrestin-biased ligands by modifying predicted ligand interactions that block TM5 interactions and promote EL2 interactions. This strategy may facilitate the structure-guided design of arrestin-biased ligands at other GPCRs, including polypharmacological biased ligands.
Author List
McCorvy JD, Butler KV, Kelly B, Rechsteiner K, Karpiak J, Betz RM, Kormos BL, Shoichet BK, Dror RO, Jin J, Roth BLAuthor
John McCorvy PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AripiprazoleCrystallography, X-Ray
Cyclic AMP
Drug Design
Drug Discovery
HEK293 Cells
Humans
Hydrogen Bonding
Indoles
Kinetics
Ligands
Molecular Dynamics Simulation
Mutation
Protein Binding
Protein Conformation
Receptors, G-Protein-Coupled
Serine
Signal Transduction
beta-Arrestin 1
