Lipid Receptor S1P1 Activation Scheme Concluded from Microsecond All-Atom Molecular Dynamics Simulations

Yuan, Shuguang; Wu, Rongliang; Latek, Dorota; Trzaskowski, Bartosz; Filipek, Sławomir

doi:10.1371/journal.pcbi.1003261

Cited by 32 publications

(57 citation statements)

References 53 publications

(46 reference statements)

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“…[6,7,21,24] The bending of transmembrane helices is another signature of GPCR activation. [25,26] Such events were observed in the present study of the 5-HT 1A receptor. As captured and quantified for the final 50 ns period of each of our MD simulations, the agonist-bound receptor underwent bending of helices TM5 ( Figures S3, S4), TM6, and TM7, which is not seen in the antagonist-bound complexes.…”

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confidence: 82%

Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT_1A Receptor

et al. 2016

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G-protein-coupled receptors (GPCRs) are involved in a wide range of physiological processes, and they have attracted considerable attention as important targets for developing new medicines. A central and largely unresolved question in drug discovery, which is especially relevant to GPCRs, concerns ligand selectivity: Why do certain molecules act as activators (agonists) whereas others, with nearly identical structures, act as blockers (antagonists) of GPCRs? To address this question, we employed all-atom, long-timescale molecular dynamics simulations to investigate how two diastereomers (epimers) of dihydrofuroaporphine bind to the serotonin 5-HT 1A receptor and exert opposite effects. By using molecular interaction fingerprints, we discovered that the agonist could mobilize nearby amino acid residues to act as molecular switches for the formation of a continuous water channel. In contrast, the antagonist epimer remained firmly stabilized in the binding pocket.The growing number of crystal structures and related computer simulations of G-protein-coupled receptors (GPCRs) have resolved a number of structural key features in the activation process of GPCRs, including ligand-binding specificity, side-chain molecular switches, rearrangement of transmembrane helices, and formation of internal water channels. [1][2][3][4][5][6][7][8][9][10] In spite of this progress, many important mechanistic principles of GPCR-mediated signalling remain poorly understood at the molecular level. An example is ligand stereoselectivity, which is a central concern in drug discovery since it substantially influences the efficacy, efficiency, and metabolic properties of drug candidates. [11,12] Molecular dynamics could be of great help towards addressing such unresolved issues. [9,10] In this work, we used all-atom, long-timescale molecular dynamics (MD) simulations to investigate the ligand stereoselectivity of the serotonin 5-HT 1A receptor and determine how the stereochemical arrangement of a single methyl group at a chiral carbon atom determines whether the ligand acts as an agonist or an antagonist.For a pair of dihydrofuroaporphine epimers, functional assays have identified one epimer to be a full agonist and the other to be a full antagonist of the serotonin 5-HT 1A receptor. [13,14] The configuration of a single methyl group is the only structural difference between this pair of diastereomers, and it results in different functional properties as ligands for the receptor (Scheme 1).To explain the structural basis of this stereoselectivity of a prototypical GPCR, we first built a homology model of the 5-HT 1A receptor by using the crystal structure of the 5-HT 1B receptor (PDB ID: 4IAQ) [15] for an agonist-bound receptor structure template and that of the M3 muscarinic receptor (PDB ID: 4U15) [16] for an antagonist-bound receptor structure template. Interestingly, the superimposed crystal structures of the two receptors are almost identical ( Figure S1 in the Supporting Information), with an RMSD of less than 1.5 for the TM backbone...

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confidence: 82%

Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT_1A Receptor

et al. 2016

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“…[25, 26] Such events were observed in the present study of the 5-HT 1A receptor. As captured and quantified for the final 50 ns period of each of our MD simulations, the agonist-bound receptor underwent bending of helices TM5 (Figures S3, S4), TM6, and TM7, which is not seen in the antagonist-bound complexes.…”

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confidence: 68%

Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT_1A Receptor

et al. 2016

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“…It involves a horizontal rotation of TM VI, thus causing rearrangement of TM III‐V‐VI interface and results in activation due to agonist binding. Similar mechanism has been recently described in molecular dynamics simulation of a lipid receptor S1P 1 …”

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confidence: 66%

Structure and dynamics of DRD4 bound to an agonist and an antagonist usingin silicoapproaches

2015

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Human dopamine receptor D4 (DRD4), a member of G-protein coupled receptor (GPCR) family, plays a central role in cell signaling and trafficking. Dysfunctional activity of DRD4 can lead to several psychiatric conditions and, therefore, represents target for many neurological disorders. However, lack of atomic structure impairs our understanding of the mechanism regulating its activity. Here, we report the modeled structure of DRD4 alone and in complex with dopamine and spiperone, its natural agonist and antagonist, respectively. To assess the conformational dynamics induced upon ligand binding, all-atom explicit solvent molecular dynamics simulations in membrane environment were performed. Comprehensive analyses of simulations reveal that agonist binding triggers a series of conformational changes in the transmembrane region, including rearrangement of residues, characteristic of transmission and tyrosine toggle molecular switches. Further, the trajectories indicate that a loop region in the intracellular region--ICL3, is significantly dynamic in nature, mainly due to the side-chain movements of conserved proline residues involved in SH3 binding domains. Interestingly, in dopamine-bound receptor simulation, ICL3 represents an open conformation ideal for G protein binding. The structural and dynamical information presented here suggest a mode of activation of DRD4, upon ligand binding. Our study will help in further understanding of receptor activation, as acquiring structural information is crucial for the design of highly selective DRD4 ligands.

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Lipid Receptor S1P1 Activation Scheme Concluded from Microsecond All-Atom Molecular Dynamics Simulations

Cited by 32 publications

References 53 publications

Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT_1A Receptor

Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT_1A Receptor

Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT_1A Receptor

Structure and dynamics of DRD4 bound to an agonist and an antagonist usingin silicoapproaches

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Lipid Receptor S1P1 Activation Scheme Concluded from Microsecond All-Atom Molecular Dynamics Simulations

Cited by 32 publications

References 53 publications

Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT1A Receptor

Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT1A Receptor

Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT1A Receptor

Structure and dynamics of DRD4 bound to an agonist and an antagonist usingin silicoapproaches

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Product

Resources

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Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT_1A Receptor

Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT_1A Receptor

Mechanistic Studies on the Stereoselectivity of the Serotonin 5‐HT_1A Receptor