Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Structural insights into subtype-specific agonist recognition by sphingosine-1-phosphate receptors.
Journal, issue, pages	PLoS Biol, Vol. 24, Issue 4, Page e3003381, Year 2026
Publish date	Apr 10, 2026
Authors	Leiye Yu / Haizhan Jiao / Bin Pang / Rujuan Ti / Bing Gan / Zhaoyang Qin / Jinxin Wang / Lizhe Zhu / Hongli Hu / Ruobing Ren /
PubMed Abstract	Sphingosine-1-phosphate (S1P), a key metabolite of sphingolipids, plays crucial roles in a wide range of physiological and pathological processes. S1P primarily exerts its functions by binding to G ...Sphingosine-1-phosphate (S1P), a key metabolite of sphingolipids, plays crucial roles in a wide range of physiological and pathological processes. S1P primarily exerts its functions by binding to G protein-coupled sphingosine-1-phosphate receptors (S1PRs), which comprise five subtypes (S1PR1-5) in humans, thereby activating these receptors and their downstream signaling pathways. Understanding the molecular determinants that govern agonist selectivity among different S1PR subtypes is vital for the rational and precise development of targeted therapeutic agents. Here, four cryo-electron microscopy structures of agonist-bound S1PR1-Gi1 complexes are reported. Through an integrated approach combining structural analysis, molecular dynamics simulations, and pharmacological assays, the molecular basis for the selectivity of CYM5442, HY-X-1011, Ponesimod, and SAR247799 toward S1PR1 over S1PR2-S1PR5 is uncovered. Nonconserved residues within the ligand-binding pocket and at the Gi1-protein interface contribute to S1PR1 selectivity by these agonists. A distinct agonist binding orientation toward transmembrane helices 5-7, combined with branched substituents that increase the agonist's molecular width, results in steric clashes with residues in S1PR3. Additionally, branched moieties located at the tail portions of the agonist restrict its deep insertion into the binding pocket of both S1PR3 and S1PR5. These structural features collectively enhance its selectivity for S1PR1 over S1PR3 and S1PR5. Furthermore, polar interactions with conserved polar residues in the top region of the binding pocket also influence agonist selectivity. Besides, the relatively broad molecular width of the agonist sterically hinders its binding into S1PR2 and S1PR4 pocket by nonconserved residue pairs bearing bulky side chains. These findings establish a structural framework for the rational design of next-generation S1PR1 highly selective agonists with improved therapeutic potential.
External links	PLoS Biol / PubMed:41961881 / PubMed Central
Methods	EM (single particle)
Resolution	2.79 - 3.69 Å
Structure data	65218 9vny EMDB-65218, PDB-9vny: Cryo-EM structure of Gi coupled Sphingosine 1-phosphate receptor bound with CYM5442 Method: EM (single particle) / Resolution: 3.69 Å 65219 9vnz EMDB-65219, PDB-9vnz: Cryo-EM structure of Gi coupled Sphingosine 1-phosphate receptor bound with HY-X-1011 Method: EM (single particle) / Resolution: 2.79 Å 65220 9vo0 EMDB-65220, PDB-9vo0: Cryo-EM structure of Gi coupled Sphingosine 1-phosphate receptor bound with Ponesimod Method: EM (single particle) / Resolution: 2.79 Å 65221 9vo1 EMDB-65221, PDB-9vo1: Cryo-EM structure of Gi coupled Sphingosine 1-phosphate receptor bound with SAR247799 Method: EM (single particle) / Resolution: 2.97 Å
Chemicals	PDB-1l3g: NMR Structure of the DNA-binding Domain of Cell Cycle Protein, Mbp1(2-124) from Saccharomyces cerevisiae PDB-1esy: NMR STRUCTURE OF STEM LOOP SL2 OF THE HIV-1 PSI RNA PACKAGING SIGNAL REVEALS A NOVEL A-U-A BASE-TRIPLE PLATFORM PDB-1esz: STRUCTURE OF THE PERIPLASMIC FERRIC SIDEROPHORE BINDING PROTEIN FHUD COMPLEXED WITH COPROGEN PDB-1lyq: Crystal Structure of PcoC, a Methionine Rich Copper Resistance Protein from Escherichia coli
Source	homo sapiens (human) mus musculus (house mouse) escherichia coli (E. coli)
Keywords	SIGNALING PROTEIN / GPCR / S1PR1