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Insights into divalent cation regulation and G₁₃-coupling of orphan receptor GPR35.

ABSTRACT: Endogenous ions play important roles in the function and pharmacology of G protein-coupled receptors (GPCRs) with limited atomic evidence. In addition, compared with G protein subtypes G_s, G_i/o, and G_q/11, insufficient structural evidence is accessible to understand the coupling mechanism of G_12/13 protein by GPCRs. Orphan receptor GPR35, which is predominantly expressed in the gastrointestinal tract and is closely related to inflammatory bowel diseases (IBDs), stands out as a prototypical receptor for investigating ionic modulation and G₁₃ coupling. Here we report a cryo-electron microscopy structure of G₁₃-coupled GPR35 bound to an anti-allergic drug, lodoxamide. This structure reveals a novel divalent cation coordination site and a unique ionic regulatory mode of GPR35 and also presents a highly positively charged binding pocket and the complementary electrostatic ligand recognition mode, which explain the promiscuity of acidic ligand binding by GPR35. Structural comparison of the GPR35-G₁₃ complex with other G protein subtypes-coupled GPCRs reveals a notable movement of the C-terminus of α5 helix of the Gα₁₃ subunit towards the receptor core and the least outward displacement of the cytoplasmic end of GPR35 TM6. A featured 'methionine pocket' contributes to the G₁₃ coupling by GPR35. Together, our findings provide a structural basis for divalent cation modulation, ligand recognition, and subsequent G₁₃ protein coupling of GPR35 and offer a new opportunity for designing GPR35-targeted drugs for the treatment of IBDs.

SUBMITTER: Duan J

PROVIDER: S-EPMC9772185 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Insights into divalent cation regulation and G13-coupling of orphan receptor GPR35.

Duan Jia J Liu Qiufeng Q Yuan Qingning Q Ji Yujie Y Zhu Shengnan S Tan Yangxia Y He Xinheng X Xu Youwei Y Shi Jingjing J Cheng Xi X Jiang Hualiang H Eric Xu H H Jiang Yi Y

Cell discovery 20221221 1

Endogenous ions play important roles in the function and pharmacology of G protein-coupled receptors (GPCRs) with limited atomic evidence. In addition, compared with G protein subtypes Gs, Gi/o, and Gq/11, insufficient structural evidence is accessible to understand the coupling mechanism of G12/13 protein by GPCRs. Orphan receptor GPR35, which is predominantly expressed in the gastrointestinal tract and is closely related to inflammatory bowel disease ...[more]

PMID: 36543774

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Project description:The G protein-coupled receptor (GPCR) superfamily of integral proteins is the largest family of signal transducers, comprised of ∼1000 members. Considering their prevalence and functional importance, it's not surprising that ∼60% of drugs target GPCRs. Regardless, there exists a subset of the GPCR superfamily that is largely uncharacterized and poorly understood; specifically, more than 140 GPCRs have unknown endogenous ligands-the so-called orphan GPCRs. Orphan GPCRs offer tremendous promise, as they may provide novel therapeutic targets that may be more selective than currently known receptors, resulting in the potential reduction in side effects. In addition, they may provide access to signal transduction pathways currently unknown, allowing for new strategies in drug design. Regardless, orphan GPCRs are an important area of inquiry, as they represent a large gap in our understanding of signal transduction at the cellular level. Here, we focus on the therapeutic potential of two recently deorphanized GPCRs: GPR35/CXCR8 and GPR55. First, GPR35/CXCR8 has been observed in numerous tissues/organ systems, including the gastrointestinal tract, liver, immune system, central nervous system, and cardiovascular system. Not surprisingly, GPR35/CXCR8 has been implicated in numerous pathologies involving these tissues/systems. While several endogenous ligands have been identified, GPR35/CXCR8 has recently been observed to bind the chemokine CXCL17. Second, GPR55 has been observed to be expressed in the central nervous system, adrenal glands, gastrointestinal tract, lung, liver, uterus, bladder, kidney, and bone, as well as, other tissues/organ systems. Likewise, it is not surprising that GPR55 has been implicated in pathologies involving these tissues/systems. GPR55 was initially deorphanized as a cannabinoid receptor and this receptor does bind many cannabinoid compounds. However, the GPR55 endogenous ligand has been found to be a non-cannabinoid, lysophophatidylinositol (LPI) and subsequent high throughput assays have identified other GPR55 ligands that are not cannabinoids and do not bind to either the cannabinoid CB1 and CB2 receptors. Here, we review reports that suggest that GPR35/CXCR8 and GPR55 may be promising therapeutic targets, with diverse physiological roles.

Dataset Information

Insights into divalent cation regulation and G₁₃-coupling of orphan receptor GPR35.

Publications

Insights into divalent cation regulation and G<sub>13</sub>-coupling of orphan receptor GPR35.

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