Endogenous agonist–bound S1PR3 structure reveals determinants of G protein–subtype bias

脂質受容体の新たな活性化機構を解明 --脂質がまっすぐ伸びて活性化--. 京都大学プレスリリース. 2021-06-10.Sphingosine-1-phosphate (S1P) regulates numerous important physiological functions, including immune response and vascular integrity, via its cognate receptors (S1PR1 to S1PR5); however, it remains unclear how S1P activates S1PRs upon binding. Here, we determined the crystal structure of the active human S1PR3 in complex with its natural agonist S1P at 3.2-Å resolution. S1P exhibits an unbent conformation in the long tunnel, which penetrates through the receptor obliquely. Compared with the inactive S1PR1 structure, four residues surrounding the alkyl tail of S1P (the “quartet core”) exhibit orchestrating rotamer changes that accommodate the moiety, thereby inducing an active conformation. In addition, we reveal that the quartet core determines G protein selectivity of S1PR3. These results offer insight into the structural basis of activation and biased signaling in G protein–coupled receptors and will help the design of biased ligands for optimized therapeutics

Structural insights into the agonists binding and receptor selectivity of human histamine H₄ receptor

慢性アレルギー疾患に関わるヒスタミン受容体の構造解明 --新規アトピー性皮膚炎・喘息治療薬の開発に貢献--. 京都大学プレスリリース. 2023-10-23.Histamine is a biogenic amine that participates in allergic and inflammatory processes by stimulating histamine receptors. The histamine H₄ receptor (H₄R) is a potential therapeutic target for chronic inflammatory diseases such as asthma and atopic dermatitis. Here, we show the cryo-electron microscopy structures of the H₄R-Gq complex bound with an endogenous agonist histamine or the selective agonist imetit bound in the orthosteric binding pocket. The structures demonstrate binding mode of histamine agonists and that the subtype-selective agonist binding causes conformational changes in Phe344[7.39], which, in turn, form the “aromatic slot”. The results provide insights into the molecular underpinnings of the agonism of H₄R and subtype selectivity of histamine receptors, and show that the H₄R structures may be valuable in rational drug design of drugs targeting the H₄R

Structure of the dopamine D2 receptor in complex with the antipsychotic drug spiperone

統合失調症に関わるドパミン受容体の構造解明 --副作用を抑えた薬の迅速な探索・設計が可能に--. 京都大学プレスリリース. 2020-12-24.In addition to the serotonin 5-HT2A receptor (5-HT2AR), the dopamine D2 receptor (D2R) is a key therapeutic target of antipsychotics for the treatment of schizophrenia. The inactive state structures of D2R have been described in complex with the inverse agonists risperidone (D2Rris) and haloperidol (D2Rhal). Here we describe the structure of human D2R in complex with spiperone (D2Rspi). In D2Rspi, the conformation of the extracellular loop (ECL) 2, which composes the ligand-binding pocket, was substantially different from those in D2Rris and D2Rhal, demonstrating that ECL2 in D2R is highly dynamic. Moreover, D2Rspi exhibited an extended binding pocket to accommodate spiperone’s phenyl ring, which probably contributes to the selectivity of spiperone to D2R and 5-HT2AR. Together with D2Rris and D2Rhal, the structural information of D2Rspi should be of value for designing novel antipsychotics with improved safety and efficacy

Regulation of the Human Ghrelin Promoter Activity by Transcription Factors, NF-κB and Nkx2.2

To examine the gene expression of ghrelin, a growth hormone releasing and appetite stimulating hormone from stomach, we constructed human ghrelin promoter-reporter vectors and analyzed the promoter activity. The ghrelin promoter activity was high when cultured cells that express ghrelin mRNA endogenously like TT or ECC10 cells were used, indicating that these cells contain factors necessary for full expression of the human ghrelin gene. The human ghrelin promoter contains both positive and negative regulatory regions. A transient decrease of the promoter activity was found when the reporter vector with the −1600 fragment of the human ghrelin promoter was transfected into cultured cells. We then examined the effect of several transcription factors on the ghrelin promoter activity and found that NF-κB suppressed and that Nkx2.2, a homeodomain-containing transcription factor that is important for ghrelin cell development in pancreas, activates the promoter activity. These transcription factors may be possible targets for the control of ghrelin gene expression

Structure of an antagonist-bound ghrelin receptor reveals possible ghrelin recognition mode

Ghrelin is a gastric peptide hormone with important physiological functions, including growth hormone release and appetite-stimulating activity. Here, authors solved the crystal structure of the ghrelin receptor bound to antagonist and suggested a possible mechanism of activation by acyl-modified ghrelin