2. Academic Validation
  3. Mechanism of GPR84 allosteric modulation at a helix 8-proximate site

Mechanism of GPR84 allosteric modulation at a helix 8-proximate site

  • bioRxiv. 2026 Apr 12:2026.04.10.715585. doi: 10.64898/2026.04.10.715585.
Xuan Zhang 1 2,  Abdul-Akim Guseinov 3 2,  Laura Jenkins 3 2,  Jingkai Zhou 4,  Fabian Gossen 5,  Pinqi Wang 6 7,  Zobaer Al Mahmud 3,  Yueming Li 3,  Andhika B Mahardhika 5,  Christa E Müller 5,  Mingye Feng 4,  Angela J Russell 6 7,  Irina G Tikhonova 8,  Graeme Milligan 3,  Cheng Zhang 1
Affiliations

Affiliations

  • 1 Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, U.S.A.
  • 2 Equal contributions.
  • 3 School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, U.K.
  • 4 Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA.
  • 5 University of Bonn, PharmaCenter Bonn & Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, An der Immenburg 4, 53121 Bonn, Germany.
  • 6 Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
  • 7 Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, U.K.
  • 8 School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, U.K.
PMID: 41993300 DOI: 10.64898/2026.04.10.715585
Abstract

Allosteric modulators offer opportunities for pathway-selective GPCR signalling, but the structural mechanisms enabling biased allosteric modulation remain unclear. Here we identify a helix 8-proximate allosteric site in the immune-metabolic receptor GPR84 and define how it achieves Gi-biased signalling. Cryo-EM structures of the GPR84-Gi complexes bound to the orthosteric agonist OX04539 alone or in combination with the positive allosteric modulator (PAM) PSB-16671 reveal that PSB-16671 binds at the interface of TM1, TM7, and helix 8, a location distinct from previously characterized GPCR allosteric pockets. 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. Unexpectedly, disrupting this network enhances allosteric cooperativity, indicating that conformational flexibility within the network is essential for allosteric communication. PSB-16671 stabilizes a receptor conformation with pronounced TM6 displacement that favours Gi coupling while disfavouring β-arrestin recruitment. This Gi-biased profile sustains macrophage phagocytosis of Cancer cells without the desensitization induced by balanced agonists. Sequence analysis suggests that helix 8-proximate allosteric sites may be broadly targetable across class A GPCRs, while receptor-specific contacts enable selective modulation. These findings establish structural and mechanistic principles for biased allosteric modulation applicable beyond GPR84.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-182723
    GPR84 激活剂
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