Unknown

Dataset Information

0

Structure-inspired design of ?-arrestin-biased ligands for aminergic GPCRs.


ABSTRACT: 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 ?-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 ?-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.

SUBMITTER: McCorvy JD 

PROVIDER: S-EPMC5771956 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

altmetric image

Publications

Structure-inspired design of β-arrestin-biased ligands for aminergic GPCRs.

McCorvy John D JD   Butler Kyle V KV   Kelly Brendan B   Rechsteiner Katie K   Karpiak Joel J   Betz Robin M RM   Kormos Bethany L BL   Shoichet Brian K BK   Dror Ron O RO   Jin Jian J   Roth Bryan L BL  

Nature chemical biology 20171211 2


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  ...[more]

Similar Datasets

| S-EPMC6058965 | biostudies-literature
| S-EPMC3764853 | biostudies-literature
| S-EPMC4707817 | biostudies-literature
| S-EPMC4394255 | biostudies-literature
| S-EPMC6682580 | biostudies-literature
| S-EPMC5350031 | biostudies-literature
| S-EPMC7614537 | biostudies-literature
| S-EPMC7176292 | biostudies-literature
| S-EPMC9118924 | biostudies-literature
| S-EPMC7873251 | biostudies-literature