Rolle des Wassers und der Natriumionen bei der Aktivierung des μ‐Opioidrezeptors

Yuan, Shuguang; Vogel, Horst; Filipek, Sławomir

doi:10.1002/ange.201302244

Angewandte Chemie

2013

DOI: 10.1002/ange.201302244

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Rolle des Wassers und der Natriumionen bei der Aktivierung des μ‐Opioidrezeptors

Shuguang Yuan

Horst Vogel

Sławomir Filipek

Abstract: Doppelter Effekt von Natriumionen: Die Aktivierung der G‐Protein‐gekoppelten Rezeptoren hängt von der Anwesenheit von Wassermolekülen innerhalb des Rezeptors und von allosterischen Wechselwirkungen ab. Mithilfe von μs‐Moleküldynamik‐Simulationen war es möglich, zu erklären, wie Natriumionen an die allosterische Bindungsstelle des μ‐Opioidrezeptors binden und scheinbar gegensätzliche Effekte hervorrufen, wie die Verminderung der Ligandenbindungsaffinität und die Erhöhung der Rezeptoraktivierung.

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Cited by 13 publications

(1 citation statement)

References 22 publications

(32 reference statements)

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“…The existence of such hydrophobic layers of amino acids agrees with the disruption of water-mediated hydrogen-bond networks observed in GPCR crystal structures [22,23] and in MD simulations. [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.…”

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

et al. 2016

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W246^6.48 Opens a Gate for a Continuous Intrinsic Water Pathway during Activation of the Adenosine A_2A Receptor

Yuan

Filipek

et al. 2014

Angewandte Chemie

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The question how G‐protein‐coupled receptors transduce an extracellular signal by a sequence of transmembrane conformational transitions into an intracellular response remains to be solved at molecular detail. Herein, we use molecular dynamics simulations to reveal distinct conformational transitions of the adenosine A2A receptor, and we found that the conserved W2466.48 residue in transmembrane helix TM6 performs a key rotamer toggle switch. Agonist binding induces the sidechain of W2466.48 to fluctuate between two distinct conformations enabling the diffusion of water molecules from the bulk into the center of the receptor. After passing the W2466.48 gate, the internal water molecules induce another conserved residue, Y2887.53, to switch to a distinct rotamer conformation establishing a continuous transmembrane water pathway. Further, structural changes of TM6 and TM7 induce local structural changes of the adjacent lipid bilayer.

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The Mechanism of Ligand‐Induced Activation or Inhibition of μ‐ and κ‐Opioid Receptors

et al. 2015

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G-protein-coupled receptors (GPCRs) are important targets for treating severe diseases.H owever why certain molecules act as activators whereas others,w ith similar structures,b lockG PCR activation, is poorly understood since the same molecule can activate one receptor subtype while blocking another closely related receptor.T os hed light on these central questions,w eu sed all-atom, long-time-scale molecular dynamics simulations on the k-opioid and m-opioid receptors (kOR and mOR). We found that water molecules penetrating into the receptor interior mediate the activating versus blocking effects of ap articular ligand-receptor interaction. Both the sizea nd the flexibility of the bound ligand regulated water influx into the receptor.The solvent-accessible inner surface area was found to be ap arameter that can help predict the function of the bound ligand.Theknowncrystalstructuresofligand-freeandligand-bound G-protein-coupled receptors (GPCRs), as well as their ternary complexes with Gproteins,s how al arge number of structural details [1] .B ased on static crystal structures and molecular dynamics simulations,s ome common elements in the activation mechanism of GPCRs have been found, including side-chain microswitches,m ovement of transmembrane helices,a nd rearrangement of internal water molecules. [2][3][4][5][6][7] Herein, we concentrate on the question of whether specific properties of GPCR ligands can be predicted from the structural features of the corresponding ligand-receptor complexes obtained from computer simulations.Levallorphan is am orphine-like drug that is widely used as an antidote and opioid modulator. [8] It acts as an agonist for k-opioid receptors (kORs) but as an antagonist for m-opioid receptors (mORs). [9] As ar esult, it blocks the effects of stronger agents with greater intrinsic activity,s uch as morphine or endogenous b-endorphin. [10] To address the different effects of levallorphan on kORs and mORs,w ef irst performed all-atom molecular dynamics (MD) simulations on the crystal structures of both the kOR (pdb:4 DJH) [11] and mOR (pdb:4 DKL) [12] (Table 1).Our previous work [6] indicated that aN a + ion from bulk water can diffuse into the allosteric site of mOR, bind to the highly conserved D114 2.50 ,a nd thereby influence receptor function. To determine whether this finding would pertain to kOR, we performed 0.5 msM Ds imulations for apo-kOR Table 1: Ligand-receptors ystemsu sed for MD simulations. Receptor kOR kOR-jdt kOR-lev mOR-lev mOR-mor Ligand -J DTic levallorphan levallorphanm orphine Function apo antagonist agonist antagonist agonist t [ms] 0.5 33 33 [*] Dr.

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Rolle des Wassers und der Natriumionen bei der Aktivierung des μ‐Opioidrezeptors

Cited by 13 publications

References 22 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

W246^6.48 Opens a Gate for a Continuous Intrinsic Water Pathway during Activation of the Adenosine A_2A Receptor

The Mechanism of Ligand‐Induced Activation or Inhibition of μ‐ and κ‐Opioid Receptors

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Rolle des Wassers und der Natriumionen bei der Aktivierung des μ‐Opioidrezeptors

Cited by 13 publications

References 22 publications

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

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

W2466.48 Opens a Gate for a Continuous Intrinsic Water Pathway during Activation of the Adenosine A2A Receptor

The Mechanism of Ligand‐Induced Activation or Inhibition of μ‐ and κ‐Opioid Receptors

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Product

Resources

About

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

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

W246^6.48 Opens a Gate for a Continuous Intrinsic Water Pathway during Activation of the Adenosine A_2A Receptor