Structural insights into sphingosine-1-phosphate receptor activation

Yu, Leiye; He, Licong; Gan, Bing Siang; Ti, Rujuan; Xiao, Qicai; Hu, Hongli; Zhu, Lizhe; Wang, Sheng; Ren, Ruobing

doi:10.1073/pnas.2117716119

Cited by 31 publications

(34 citation statements)

References 38 publications

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“…Protein preparation. In this study, EGFR, S1PR1 and HTR1A were used as the target proteins [ 32 , 34 , 35 ]. The crystal structure of the protein was downloaded and used from the RCSB Protein Data Bank (PDB) dataset.…”

Section: Methodsmentioning

confidence: 99%

“…Existing methods face the problem of data scarcity in the development of drugs against EGFR. As a critical sphingolipid metabolite, sphingosine-1-phosphate (S1P) plays an essential role in immune and vascular systems [ 34 ]. 5-HT receptors have high levels of basal activity and are subject to regulation by lipids, but the structural basis for the lipid regulation and basal activation of these receptors and the pan-agonism of 5-HT remains unclear [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

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PETrans: De Novo Drug Design with Protein-Specific Encoding Based on Transfer Learning

Wang

Gao

Han

et al. 2023

IJMS

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Recent years have seen tremendous success in the design of novel drug molecules through deep generative models. Nevertheless, existing methods only generate drug-like molecules, which require additional structural optimization to be developed into actual drugs. In this study, a deep learning method for generating target-specific ligands was proposed. This method is useful when the dataset for target-specific ligands is limited. Deep learning methods can extract and learn features (representations) in a data-driven way with little or no human participation. Generative pretraining (GPT) was used to extract the contextual features of the molecule. Three different protein-encoding methods were used to extract the physicochemical properties and amino acid information of the target protein. Protein-encoding and molecular sequence information are combined to guide molecule generation. Transfer learning was used to fine-tune the pretrained model to generate molecules with better binding ability to the target protein. The model was validated using three different targets. The docking results show that our model is capable of generating new molecules with higher docking scores for the target proteins.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PETrans: De Novo Drug Design with Protein-Specific Encoding Based on Transfer Learning

Wang

Gao

Han

et al. 2023

IJMS

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“…The scFv16 with a C-terminal 8×His tag was expressed in Trichoplusia ni Hi5 insect cells and purified precisely as previously described[27, 39, 40]. Briefly, the Hi5 insect cells (3.0-4.0 million cells per ml) were infected with the scFv16 virus produced by the Bac-to-Bac system (Invitrogen) for 96h.…”

Section: Methodsmentioning

confidence: 99%

“…BRET assays[50] were performed as previously reported[39] to measure MRGPRX1-mediated G q protein activation. Briefly, HEK293T cells (ATCCCRL-11268; mycoplasma free) were co-transfected at a 1:1:1:1 ratio of receptor: G αq -Rluc8: G β : G γ -GFP2.…”

Section: Methodsmentioning

confidence: 99%

The structural basis of itch receptor MRGPRX1 activation

Gan

Yang

et al. 2022

Preprint

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Mas-related G-protein-coupled receptors X1-X4 (MRGPRX1-X4) are four primate-specific receptors that are recently reported to be responsible for many biological processes, including itch sensation, pain transmission, and inflammatory reactions. MRGPRX1 is the first identified human MRGPR, and its expression is restricted to primary sensory neurons. Due to its dual roles in itch and pain signaling pathways, MRGPRX1 has been regarded as a promising target for itch remission and pain inhibition. Here, we reported a cryo-electron microscopy (cryo-EM) structure of Gq-coupled MRGPRX1 in complex with a synthetic agonist compound 16 in an active conformation at an overall resolution of 3.0 angstrom via a NanoBiT tethering strategy. Compound 16 is a new pain-relieving compound with high potency and selectivity to MRGPRX1 over opioid receptor. According to the structure analysis, we revealed that MRGPRX1 shares common features of the Gq-mediated receptor activation mechanism of MRGPRX family members. However, the variable residues in orthosteric pocket of MRGPRX1 exhibits the unique agonist recognition pattern, which may facilitate to design MRGPRX1-specific modulators. Together with receptor activation and itch behavior evaluation assays, our study provides a structural snapshot to modify therapeutic molecules for itch relieving and analgesia targeting MRGPRX1.

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“…Recently, cryogenic electron microscopy (cryo-EM) structures of S1PR1 complexed with different small molecule ligands have been determined [18][19][20][21] . These findings reveal a mechanism of how S1PR1 engages its endogenous ligand S1P and its modulators to adopt the active conformation for recruiting the heterotrimeric Gi protein.…”

Section: Mainmentioning

confidence: 99%

Transmembrane protein CD69 acts as an S1PR1 agonist

Chen

Chou

et al. 2023

Preprint

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The activation of Sphingosine-1-phosphate receptor 1 (S1PR1) by S1P promotes lymphocyte egress from lymphoid organs, a process critical for immune surveillance and T cell effector activity. Multiple drugs that inhibit S1PR1 function are in use clinically for the treatment of autoimmune diseases. Cluster of Differentiation 69 (CD69) is an endogenous negative regulator of lymphocyte egress that interacts with S1PR1 incisto facilitate internalization and degradation of the receptor. The mechanism by which CD69 causes S1PR1 internalization has been unclear. Moreover, although there are numerous class A GPCR structures determined with different small molecule agonists bound, it remains unknown whether a transmembrane protein per se can act as a class A GPCR agonist. Here, we present the cryo-EM structure of CD69-bound S1PR1 coupled to the heterotrimeric Gicomplex. The transmembrane helix (TM) of one protomer of CD69 homodimer contacts the S1PR1-TM4. This interaction allosterically induces the movement of S1PR1-TMs 5-6, directly activating the receptor to engage the heterotrimeric Gi. Mutations in key residues at the interface affect the interactions between CD69 and S1PR1, as well as reduce the receptor internalization. Thus, our structural findings along with functional analyses demonstrate that CD69 acts incisas a protein agonist of S1PR1, thereby promoting Gi-dependent S1PR1 internalization, loss of S1P gradient sensing, and inhibition of lymphocyte egress.

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Structural insights into sphingosine-1-phosphate receptor activation

Cited by 31 publications

References 38 publications

PETrans: De Novo Drug Design with Protein-Specific Encoding Based on Transfer Learning

PETrans: De Novo Drug Design with Protein-Specific Encoding Based on Transfer Learning

The structural basis of itch receptor MRGPRX1 activation

Transmembrane protein CD69 acts as an S1PR1 agonist

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