Inflammatory bowel disease (IBD) mainly includes ulcerative colitis (UC) and Crohn's disease (Crohn's disease, CD). It is a type of chronic, non-specific intestinal inflammatory disease with an unknown cause. It is incurable, lifelong relapsing and disabling. In recent years, the incidence of IBD in my country has increased year by year. Currently, the inflammatory response of IBD patients is mainly alleviated through immunomodulators, glucocorticoids, , etc., or surgical removal of damaged parts of the gastrointestinal tract. There is no effective IBD treatment drug.
GPR35 is a type of G protein-coupled receptor that is highly expressed in the gastrointestinal tract. It plays a key role in regulating gastrointestinal homeostasis and is closely related to the inflammatory process, pain, and the occurrence and development of gastric cancer . According to research reports, GPR35 signal downregulation is closely related to IBDs, and its T108M mutant significantly increases the risk of IBDs. Therefore, GPR35 is considered to be one of the potential drug targets for the treatment of IBD. GPR35 can be activated by tryptophan, metabolic kynurenic acid, 5-hydroxyindoleacetic acid, lysophosphatidic acid, and the chemokine CXCL17 under physiological conditions. Due to the weak activation ability of these ligands , GPR35 is currently still defined as an orphan receptor. Anti-allergic drugs (such as lodosamide) can also efficiently activate GPR35, but their mechanism of recognizing and regulating GPR35 is still unclear.
On December 21, Researcher Xu Huaqiang of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and researcher Jiang Yi published the latest research results titled Insights into divalent cation regulation and G13-coupling of orphan receptor GPR35 on Cell Discovery. The research team solved the cryo-electron microscopy structure of the complex of GPR35 bound to lodosamide and the downstream G13 protein, with a resolution of 3.2 Angstroms (Figure 1). This result revealed for the first time the special polar positive binding pocket of GPR35, identified new binding sites and allosteric regulation modes for divalent metal ions, and clarified the molecular mechanism by which lodoxamine recognizes and activates GPR35. The study further revealed the regulatory mechanism of IBD-related mutations T108M and V76M on GPR35 activity, identified the methionine pocket at the interaction interface between the receptor and G13 protein, and revealed the molecular mechanism by which GPR35 selectively recognizes G13 protein. These results have deepened people's understanding of the basic biological issues of GPR35 ligand recognition and functional regulation, and also laid a structural foundation for the design of IBD therapeutic drugs targeting GPR35.
Figure 1 a-b. Structure of the complex between lodosamine and GPR35 and G13 proteins; c. Polar positive binding pocket of GPR35; d. Interaction interface between divalent ions and receptors and lodosamine; e. Details of the interaction interface between GPR35 and lodosamine.
Source: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
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