scholarly journals Structural Insights into Sphingosine-1-phosphate Receptor Activation

2022 ◽  
Author(s):  
Leiye Yu ◽  
Licong He ◽  
Bing Gan ◽  
Rujuan Ti ◽  
Qingjie Xiao ◽  
...  
Keyword(s):  
Transition Process ◽  
Receptor Activation ◽  
Activation Mechanism ◽  
Structural Basis ◽  
Lymphoid Tissues ◽  
Binding Modes ◽  
Dynamic Simulations ◽  
S1p Receptors ◽  
Sphingosine 1 Phosphate ◽  
Key Steps

As a critical sphingolipid metabolite, sphingosine-1-phosphate (S1P) plays an essential role in immune and vascular systems. There are five S1P receptors, designated as S1PR1-5, encoded in the human genome, and their activities are governed by endogenous S1P, lipid-like S1P mimics, or non-lipid-like therapeutic molecules. Among S1PRs, S1PR1 stands out due to its non-redundant functions, such as the egress of T and B cells from the thymus and secondary lymphoid tissues, making it a potential therapeutic target. However, the structural basis of S1PR1 activation and regulation by various agonists remains unclear. Here we reported four atomic resolution cryo-EM structures of Gi-coupled human S1PR1 complexes: bound to endogenous agonist d18:1 S1P, benchmark lipid-like S1P mimic phosphorylated Fingolimod ((S)-FTY720-P), or non-lipid-like therapeutic molecule CBP-307 in two binding modes. Our results revealed the similarities and differences of activation of S1PR1 through distinct ligands binding to the amphiphilic orthosteric pocket. We also proposed a two-step "shallow to deep" transition process of CBP-307 for S1PR1 activation. Both binding modes of CBP-307 could activate S1PR1, but from shallow to deep transition may trigger the rotation of the N-terminal helix of Gαi and further stabilize the complex by increasing the Gαi interaction with the cell membrane. We combine with extensive biochemical analysis and molecular dynamic simulations to suggest key steps of S1P binding and receptor activation. The above results decipher the common feature of the S1PR1 agonist recognition and activation mechanism and will firmly promote the development of therapeutics targeting S1P receptors.

Characterizing the interaction modes of PAR4 receptor with agonist and antagonist by molecular simulation approach

2019 ◽  
Vol 18 (02) ◽  
pp. 1950008
Author(s):  
Nan Lu ◽  
Fancui Meng ◽  
Jing Yuan ◽  
Lei Liu ◽  
Yanshi Wang ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Molecular Design ◽  
Binding Free Energy ◽  
Structural Characteristics ◽  
Principal Component ◽  
Activation Mechanism ◽  
Binding Modes ◽  
Dynamic Simulations ◽  
Extracellular Region ◽  
Agonist And Antagonist

Protease-activated receptor 4 (PAR4) is a promising target for antiplatelet therapy. In this study, homology modeling and molecular docking methods were used to investigate the binding modes of PAR4 agonists and antagonists. The outcomes show that agonists have good docking scores, and they also form more hydrogen bonds with PAR4 than antagonists. To reveal the different conformational changes caused by agonist and antagonist, molecular dynamic simulations were carried out on three selected PAR4 systems. Simulation results show that PAR4 activation involves breaking interactions of 3–7 lock switch (Try157 and Tyr322) and ionic lock switch (Arg188 and Asp173), and formation of transmission switch among Tyr161, Asn300 and Phe296. In addition, principal component analysis (PCA) indicates that the major change for agonist bound system takes place in the intracellular region while that for antagonist bound system is in the extracellular region. The binding free energy of BMS-986120 is much lower than AYPGKF, suggesting high affinity of antagonist. Moreover, the electronegative aspartic residues Asp230 and Asp235 at ECL2 are important for PAR4 binding to agonist. Clarifying the PAR4 structural characteristics may be helpful to understand the activation mechanism, giving insights into the molecular design and discovery of novel potential PAR4 antagonists in the future.

scholarly journals Conserved Residues Control the T1R3-Specific Allosteric Signaling Pathway of the Mammalian Sweet-Taste Receptor

2019 ◽  
Vol 44 (5) ◽  
pp. 303-310 ◽  
Author(s):  
Jean-Baptiste Chéron ◽  
Amanda Soohoo ◽  
Yi Wang ◽  
Jérôme Golebiowski ◽  
Serge Antonczak ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Taste Receptor ◽  
Receptor Activation ◽  
Sweet Taste ◽  
Site Directed Mutagenesis ◽  
Activation Mechanism ◽  
Structural Basis ◽  
Directed Mutagenesis ◽  
Conserved Residues ◽  
Sweet Taste Receptor

Abstract Mammalian sensory systems detect sweet taste through the activation of a single heteromeric T1R2/T1R3 receptor belonging to class C G-protein-coupled receptors. Allosteric ligands are known to interact within the transmembrane domain, yet a complete view of receptor activation remains elusive. By combining site-directed mutagenesis with computational modeling, we investigate the structure and dynamics of the allosteric binding pocket of the T1R3 sweet-taste receptor in its apo form, and in the presence of an allosteric ligand, cyclamate. A novel positively charged residue at the extracellular loop 2 is shown to interact with the ligand. Molecular dynamics simulations capture significant differences in the behavior of a network of conserved residues with and without cyclamate, although they do not directly interact with the allosteric ligand. Structural models show that they adopt alternate conformations, associated with a conformational change in the transmembrane region. Site-directed mutagenesis confirms that these residues are unequivocally involved in the receptor function and the allosteric signaling mechanism of the sweet-taste receptor. Similar to a large portion of the transmembrane domain, they are highly conserved among mammals, suggesting an activation mechanism that is evolutionarily conserved. This work provides a structural basis for describing the dynamics of the receptor, and for the rational design of new sweet-taste modulators.

scholarly journals Deciphering PD1 activation mechanism from molecular docking and molecular dynamic simulations

2021 ◽  
Author(s):  
Luis F. Ponce ◽  
Daniel P. Ramirez-Echemendia ◽  
Kalet Leon ◽  
Pedro A. Valiente
Keyword(s):  
T Cells ◽  
Molecular Docking ◽  
Cellular Membrane ◽  
Umbrella Sampling ◽  
Activation Mechanism ◽  
Binding Modes ◽  
Dynamic Simulations ◽  
Linear Lattice ◽  
High Molecular Weight Complex ◽  
Inhibitory Mechanisms

AbstractThe activation of T cells is normally accompanied by inhibitory mechanisms within which the PD1 receptor stands out. Upon binding the ligands PDL1 and PDL2, PD1 drives T cells to an unresponsive state called exhaustion characterized by a markedly decreased capacity to exert effector functions. For this reason, PD1 has become one of the most important targets in cancer immunotherapy. Despite the numerous studies about PD1 signaling modulation, how the PD1 signaling is activated upon the ligands’ binding remains an open question. Several experimental facts suggest that the activation of the PD1-PLD1 pathway depends on the interaction with an unknown partner at the cellular membrane. In this work, we investigate the possibility that the target of PD1-PDL1 is the same PD1-PDL1 complex. We combined molecular docking to explore different binding modes with molecular dynamics and umbrella sampling simulations to assess the complexes’ stability. We found a high molecular weight complex that explains the activation of PD1 upon PDL1 binding. This complex has an affinity comparable to the PD1-PDL1 interaction and resembles the form of a linear lattice.

scholarly journals Structural basis for chemokine recognition and receptor activation of chemokine receptor CCR5

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hui Zhang ◽  
Kun Chen ◽  
Qiuxiang Tan ◽  
Qiang Shao ◽  
Shuo Han ◽  
...  
Keyword(s):  
Chemokine Receptor ◽  
Immune Surveillance ◽  
Receptor Activation ◽  
Structural Basis ◽  
Tryptophan Residue ◽  
Toggle Switch ◽  
Binding Modes ◽  
Extracellular Region ◽  
Chemokine Receptor Ccr5 ◽  
Receptor Ccr5

AbstractThe chemokine receptor CCR5 plays a vital role in immune surveillance and inflammation. However, molecular details that govern its endogenous chemokine recognition and receptor activation remain elusive. Here we report three cryo-electron microscopy structures of Gi1 protein-coupled CCR5 in a ligand-free state and in complex with the chemokine MIP-1α or RANTES, as well as the crystal structure of MIP-1α-bound CCR5. These structures reveal distinct binding modes of the two chemokines and a specific accommodate pattern of the chemokine for the distal N terminus of CCR5. Together with functional data, the structures demonstrate that chemokine-induced rearrangement of toggle switch and plasticity of the receptor extracellular region are critical for receptor activation, while a conserved tryptophan residue in helix II acts as a trigger of receptor constitutive activation.

scholarly journals Correlated motions of conserved polar motifs lay out a plausible mechanism of G protein-coupled receptor activation.

2020 ◽  
Author(s):  
Argha Mitra ◽  
Arijit Sarkar ◽  
Marton Richard Szabo ◽  
Attila Borics
Keyword(s):  
G Protein ◽  
Intracellular Signaling ◽  
Transmembrane Helix ◽  
Receptor Activation ◽  
Current Theory ◽  
Activation Mechanism ◽  
Structural Basis ◽  
Binding Interface ◽  
Gpcr Activation ◽  
G Protein Coupled

Recent advancements in the field of experimental structural biology have provided high-resolution structures of active and inactive state G protein-coupled receptors (GPCRs), a highly important pharmaceutical target family, but the process of transition between these states is poorly understood. According to the current theory, GPCRs exist in structurally distinct, dynamically interconverting functional states of which populations are shifted upon binding of ligands and intracellular signaling proteins. However, explanation of the activation mechanism on an entirely structural basis gets complicated when multiple activation pathways and active receptor states are considered. Our unbiased, atomistic molecular dynamics simulations of the mu-opioid receptor in a physiological environment revealed that external stimulus is propagated to the intracellular surface of the receptor through subtle, concerted movements of highly conserved polar amino acid side chains along the 7th transmembrane helix. To amend the widely accepted theory we suggest that the initiation event of GPCR activation is the shift of macroscopic polarization between the ortho- and allosteric binding pockets and the intracellular G protein-binding interface.

scholarly journals ST-2191, an Anellated Bismorpholino Derivative of Oxy-Fingolimod, Shows Selective S1P1 Agonist and Functional Antagonist Potency In Vitro and In Vivo

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5134
Author(s):  
Bisera Stepanovska Tanturovska ◽  
Aleksandra Zivkovic ◽  
Faik Imeri ◽  
Thomas Homann ◽  
Burkhard Kleuser ◽  
...  
Keyword(s):  
Sphingosine Kinase ◽  
Lymphoid Tissues ◽  
Cell Trafficking ◽  
T Cell Trafficking ◽  
Sphingosine Kinase 2 ◽  
S1p Receptors ◽  
Sphingosine 1 Phosphate ◽  
Lymphocyte Number

Sphingosine 1-phosphate (S1P) is an extensively studied signaling molecule that contributes to cell proliferation, survival, migration and other functions through binding to specific S1P receptors. The cycle of S1P1 internalization upon S1P binding and recycling to the cell surface when local S1P concentrations are low drives T cell trafficking. S1P1 modulators, such as fingolimod, disrupt this recycling by inducing persistent S1P1 internalization and receptor degradation, which results in blocked egress of T cells from the secondary lymphoid tissues. The approval of these compounds for the treatment of multiple sclerosis has placed the development of S1PR modulators in the focus of pharmacological research, mostly for autoimmune indications. Here, we report on a novel anellated bismorpholino derivative of oxy-fingolimod, named ST-2191, which exerts selective S1P1 agonist and functional antagonist potency. ST-2191 is also effective in reducing the lymphocyte number in mice, and this effect is not dependent on phosphorylation by sphingosine kinase 2 for activity. These data show that ST-2191 is a novel S1P1 modulator, but further experiments are needed to analyze the therapeutic impact of ST-2191 in animal models of autoimmune diseases.

scholarly journals Molecular dynamics of C99-bound γ-secretase reveal two binding modes with distinct compactness, stability, and active-site retention: implications for Aβ production

2019 ◽  
Vol 476 (7) ◽  
pp. 1173-1189 ◽  
Author(s):  
Budheswar Dehury ◽  
Ning Tang ◽  
Kasper P. Kepp
Keyword(s):  
Structural Basis ◽  
Binding Modes ◽  
Wild Type ◽  
Dynamic Simulations ◽  
Aβ Peptides ◽  
Cryo Electron Microscopy ◽  
Compact State ◽  
Β Sheet ◽  
Aβ Production

Abstract The membrane protease γ-secretase cleaves the C99 fragment of the amyloid precursor protein, thus producing the Aβ peptides central to Alzheimer's disease. Cryo-electron microscopy has provided the topology but misses the membrane and loop parts that contribute to substrate binding. We report here an essentially complete atomic model of C99 within wild-type γ-secretase that respects all the experimental constraints and additionally describes loop, helix, and C99 substrate dynamics in a realistic all-atom membrane. Our model represents the matured auto-cleaved state required for catalysis. From two independent 500-ns molecular dynamic simulations, we identify two conformation states of C99 in equilibrium, a compact and a loose state. Our simulations provide a basis for C99 processing and Aβ formation and explain the production of longer and shorter Aβ, as the compact state retains C99 for longer and thus probably trims to shorter Aβ peptides. We expect pathogenic presenilin mutations to stabilize the loose over the compact state. The simulations detail the role of the Lys53–Lys54–Lys55 anchor for C99 binding, a loss of helicity of bound C99, and positioning of Thr48 and Leu49 leading to alternative trimming pathways on opposite sides of the C99 helix in three amino acid steps. The C99 binding topology resembles that of C83-bound γ-secretase without membrane but lacks a presenilin 1-C99 β-sheet, which could be induced by C83's stronger binding. The loose state should be selectively disfavored by γ-secretase modulators to increase C99 trimming and reduce the formation of longer Aβ, a strategy that is currently much explored but has lacked a structural basis.

scholarly journals Lysophospholipid (S1P) receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Victoria Blaho ◽  
Jerold Chun ◽  
Deepa Jonnalagadda ◽  
Yasuyuki Kihara ◽  
Hirotaka Mizuno ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Radioligand Binding ◽  
Cell Types ◽  
Receptor Activation ◽  
Multiple Organ ◽  
S1p Receptors ◽  
Organ Systems ◽  
Sphingosine 1 Phosphate ◽  
Heterologous Expression Systems

Sphingosine 1-phosphate (S1P) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid receptors [70]) are activated by the endogenous lipid sphingosine 1-phosphate (S1P). Originally cloned as orphan members of the endothelial differentiation gene (edg) family, current gene names have been designated as S1P1R through S1P5R [52]. S1PRs, particularly S1P1, are expressed throughout all mammalian organ systems. Ligand delivery occurs via two known carriers (or "chaperones"): albumin and HDL-bound apolipoprotein M (ApoM), the latter of which elicits biased agonist signaling by S1P1 in multiple cell types [15, 39]. The five S1PRs, two chaperones, and active cellular metabolism have complicated analyses of receptor ligand binding in native systems. Signaling pathways and physiological roles have been characterized through radioligand binding in heterologous expression systems, targeted deletion of the different S1PRs, and most recently, mouse models that report in vivo S1P1R activation [74, 76]. A crystal structure of an S1P1-T4 fusion protein confirmed aspects of ligand binding, specificity, and receptor activation determined previously through biochemical and genetic studies [48, 14]. fingolimod (FTY720), the first drug to target any of the lysophospholipid receptors, binds to four of the five S1PRs, and was the first oral therapy for multiple sclerosis [26]. The mechanisms of action of fingolimod and other S1PR modulating drugs in development include binding S1PRs in multiple organ systems, e.g., immune and nervous systems, although the precise nature of their receptor interactions requires clarification [107, 28, 43, 44].

FTY720 suppresses humoral immunity by inhibiting germinal center reaction

Blood ◽  
2004 ◽  
Vol 104 (13) ◽  
pp. 4129-4133 ◽  
Author(s):  
Shuhua Han ◽  
Xuejun Zhang ◽  
Gangdou Wang ◽  
Hui Guan ◽  
Gabriela Garcia ◽  
...  
Keyword(s):  
Immune Responses ◽  
Humoral Immunity ◽  
Germinal Center ◽  
Molecular Targets ◽  
Immunoglobulin M ◽  
Lymphoid Tissues ◽  
Germinal Center Reaction ◽  
S1p Receptors ◽  
Sphingosine 1 Phosphate ◽  
Available Information

Abstract FTY720 is a novel immunosuppressant that is highly effective in inhibiting rejection of allografts and autoimmunity in various animal models. It has been shown that the sphingosine 1 phosphate (S1P) receptors are the direct molecular targets of FTY720. However, the mechanisms responsible for inhibiting specific immune responses by FTY720 are not well resolved. In particular, there is no available information on whether or how this compound affects humoral immunity. We have investigated the effect of FTY720 treatment on B-cell response during the immune response to a well-defined T-dependent antigen. Our data demonstrated that germinal center reaction was significantly reduced in peripheral lymphoid tissues of mice treated with FTY720. In addition, FTY720 treatment inhibited the production of high-affinity, class-switched antibodies, but not the production of low-affinity, immunoglobulin M (IgM) antibody. Consistently, FTY720 did not have a significant effect on antibody response to a T-independent antigen. Our results may have important implications in application of FTY720 in immune regulation. (Blood. 2004; 104:4129-4133)

scholarly journals Lysophospholipid (S1P) receptors (version 2020.5) in the IUPHAR/BPS Guide to Pharmacology Database

2020 ◽  
Vol 2020 (5) ◽  
Author(s):  
Victoria Blaho ◽  
Jerold Chun ◽  
Danielle Jones ◽  
Deepa Jonnalagadda ◽  
Yasuyuki Kihara ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Radioligand Binding ◽  
Cell Types ◽  
Receptor Activation ◽  
Multiple Organ ◽  
S1p Receptors ◽  
Organ Systems ◽  
Sphingosine 1 Phosphate ◽  
Heterologous Expression Systems

Sphingosine 1-phosphate (S1P) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid receptors [86]) are activated by the endogenous lipid sphingosine 1-phosphate (S1P). Originally cloned as orphan members of the endothelial differentiation gene (edg) family, current gene names have been designated as S1P1R through S1P5R [66, 16, 109]. S1PRs, particularly S1P1, are expressed throughout all mammalian organ systems. Ligand delivery occurs via two known carriers (or "chaperones"): albumin and HDL-bound apolipoprotein M (ApoM), the latter of which elicits biased agonist signaling by S1P1 in multiple cell types [18, 48]. The five S1PRs, two chaperones, and active cellular metabolism have complicated analyses of receptor ligand binding in native systems. Signaling pathways and physiological roles have been characterized through radioligand binding in heterologous expression systems, targeted deletion of the different S1PRs, and most recently, mouse models that report in vivo S1P1R activation [91, 93]. A crystal structure of an S1P1-T4 fusion protein confirmed aspects of ligand binding, specificity, and receptor activation determined previously through biochemical and genetic studies [62, 17]. fingolimod (FTY720), the first drug to target any of the lysophospholipid receptors, binds to four of the five S1PRs, and was the first oral therapy for multiple sclerosis )MS) [32]. siponimod and ozanimod that target S1P1 and S1P5 are also FDA approved for the treatment of various MS forms [16, 109]. The mechanisms of action of fingolimod and other S1PR modulating drugs in development include binding S1PRs in multiple organ systems, e.g., immune and nervous systems, although the precise nature of their receptor interactions requires clarification [126, 34, 56, 57].

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