Authors
Xuan Zhang, Abdul-Akim Guseinov, Laura Jenkins, Jingkai Zhou, Fabian Gossen, Pinqi Wang, Zobaer Al Mahmud, Yueming Li, Andhika B Mahardhika, Christa E Müller, Mingye Feng, Angela J Russell, Irina G Tikhonova, Graeme Milligan, Cheng Zhang
Published in
Science advances. Volume 12. Issue 39. Pages eaeh5849. Sep 25, 2026. Epub Sep 23, 2026.
Abstract
Allosteric modulators offer opportunities for pathway-selective G protein-coupled receptor (GPCR) signaling, but the mechanisms enabling biased allosteric modulation remain poorly understood. We identify a helix 8-proximate allosteric site in the immune-metabolic receptor GPR84 and define how it achieves Gi-biased signaling. Cryo-electron microscopy structures of the GPR84-Gi complexes bound to the orthosteric agonist OX04539 alone or with the positive allosteric modulator PSB-16671 reveal a helix 8-proximate allosteric site for PSB-16671 formed between transmembrane helices 1 (TM1) and TM7. Molecular dynamics simulations and mutagenesis uncover a polar interaction network linking orthosteric and allosteric sites through conserved residues including Asp662.50, Asn1043.36, and Asn3627.45, and disrupting this network enhances allosteric cooperativity. PSB-16671 stabilizes a receptor conformation with pronounced TM6 displacement that favors Gi coupling while disfavoring β-arrestin recruitment, sustaining macrophage phagocytosis of cancer cells without the desensitization induced by balanced agonists. Sequence analysis suggests that receptor-specific helix 8-proximate allosteric sites may be broadly targetable across class A GPCRs. These findings establish mechanistic principles for biased allosteric modulation applicable beyond GPR84.
PMID:
42777063
Bibliographic data and abstract were imported from PubMed on 24 Sep 2026.
Read full publication at:
Please sign in
to see all details.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 40
- Comments 0