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-Structure paper
タイトル | Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate. |
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ジャーナル・号・ページ | Nat Commun, Vol. 13, Issue 1, Page 731, Year 2022 |
掲載日 | 2022年2月8日 |
著者 | Shian Liu / Navid Paknejad / Lan Zhu / Yasuyuki Kihara / Manisha Ray / Jerold Chun / Wei Liu / Richard K Hite / Xin-Yun Huang / |
PubMed 要旨 | Lysophospholipids are bioactive lipids and can signal through G-protein-coupled receptors (GPCRs). The best studied lysophospholipids are lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). ...Lysophospholipids are bioactive lipids and can signal through G-protein-coupled receptors (GPCRs). The best studied lysophospholipids are lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). The mechanisms of lysophospholipid recognition by an active GPCR, and the activations of lysophospholipid GPCR-G-protein complexes remain unclear. Here we report single-particle cryo-EM structures of human S1P receptor 1 (S1P) and heterotrimeric G complexes formed with bound S1P or the multiple sclerosis (MS) treatment drug Siponimod, as well as human LPA receptor 1 (LPA) and G complexes in the presence of LPA. Our structural and functional data provide insights into how LPA and S1P adopt different conformations to interact with their cognate GPCRs, the selectivity of the homologous lipid GPCRs for S1P versus LPA, and the different activation mechanisms of these GPCRs by LPA and S1P. Our studies also reveal specific optimization strategies to improve the MS-treating S1P-targeting drugs. |
リンク | Nat Commun / PubMed:35136060 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.6 - 3.11 Å |
構造データ | EMDB-25819, PDB-7td0: EMDB-25820, PDB-7td1: EMDB-25821, PDB-7td2: EMDB-25822, PDB-7td3: EMDB-25823, PDB-7td4: |
化合物 | ChemComp-NKP: ChemComp-S1P: ChemComp-NAG: ChemComp-J8C: |
由来 |
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キーワード | MEMBRANE PROTEIN / GPCR / complex / lipid |