Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors

  title={Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptors},
  author={Jie Yin and Kerim Babaoglu and Chad A. Brautigam and Lindsay D Clark and Zhenhua Shao and Thomas H. Scheuermann and Charles M. Harrell and Anthony L Gotter and Anthony J. Roecker and Christopher J Winrow and John J. Renger and Paul J. Coleman and Daniel M. Rosenbaum},
  journal={Nature Structural \&Molecular Biology},
The orexin (also known as hypocretin) G protein–coupled receptors (GPCRs) regulate sleep and other behavioral functions in mammals, and are therapeutic targets for sleep and wake disorders. The human receptors hOX1R and hOX2R, which are 64% identical in sequence, have overlapping but distinct physiological functions and potential therapeutic profiles. We determined structures of hOX1R bound to the OX1R-selective antagonist SB-674042 and the dual antagonist suvorexant at 2.8-Å and 2.75… 

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The potential of structure-based drug design to develop more subtype-selective GPCR ligands with potentially reduced side effects and provides an attractive probe molecule and lead compound is demonstrated.

The Human Orexin/Hypocretin Receptor Crystal Structures.

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Pharmacophore Model To Discover OX1 and OX2 Orexin Receptor Ligands.

A pharmacophore model trained on ∼200 antagonists and prospectively validated by screening a collection of ∼137,000 compounds is reported, finding two subpockets are important for activation in the OX1 and OX2 receptor system.

Structure-Based Discovery of Novel Ligands for the Orexin 2 Receptor.

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Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant

The structure reveals how suvorexant adopts a π-stacked horseshoe-like conformation and binds to the receptor deep in the orthosteric pocket, stabilizing a network of extracellular salt bridges and blocking transmembrane helix motions necessary for activation.

Mapping the Binding Pocket of Dual Antagonist Almorexant to Human Orexin 1 and Orexin 2 Receptors: Comparison with the Selective OX1 Antagonist SB-674042 and the Selective OX2 Antagonist N-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (EMPA)

Despite high similarities in the ligand-binding pockets of OX1 and OX2 and numerous aromatic/hydrophobic interactions, the local conformation of helix positions 3.32, 3.33, and 3.36 in transmembrane domain 3 and 45.51 in ECL2b provide the structural basis for pharmacologic selectivity between OX ones and two different antagonists for the same receptor.

Study of human Orexin-1 and -2 G-protein-coupled receptors with novel and published antagonists by modeling, molecular dynamics simulations, and site-directed mutagenesis.

It is demonstrated how even small differences in the amino acid sequences of GPCRs can lead to significant differences in structure, antagonist binding affinity, and selectivity of these receptors.

Truncated Orexin Peptides: Structure-Activity Relationship Studies.

The goal of this study was to further investigate the structure-activity relationships of these peptides and to identify truncated form of the orexin peptides active at OX1.

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Based on the publication of recent non‐clinical and clinical data, orexin receptor antagonists potentially represent a targeted, effective and well‐tolerated new class of medications for insomnia.

Structure of the agonist-bound neurotensin receptor

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GPCR Engineering Yields High-Resolution Structural Insights into β2-Adrenergic Receptor Function

Analysis of adrenergic receptor ligand-binding mutants within the context of the reported high-resolution structure of β2AR-T4L provides insights into inverse-agonist binding and the structural changes required to accommodate catecholamine agonists.