Molecular recognition of morphine and fentanyl by the human μ-opioid receptor

Zhuang, Yahui; Wang, Yue; He, Bin; He, Xinheng; Zhou, Xin; Guo, Shimeng; Rao, Qidi; Yang, Jiaqi; Liu, Jinyu; Zhou, Qingtong; Wang, Xiaoxi; Liu, Mingliang; Liu, Weiyi; Jiang, Xiangrui; Yang, Dehua; Jiang, Hualiang; Shen, Jingshan; Melcher, Karsten; Chen, Hong; Jiang, Yi; Cheng, Xi; Wang, Mingwei; Xie, Xin; Xu, H. Eric

doi:10.1016/j.cell.2022.09.041

Cited by 123 publications

(143 citation statements)

References 84 publications

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“…In the ET B -G i complex, the downward movements of the residues are larger than those in the ET-1-bound crystal structure (Figure 2B), resulting in the outward displacement of the intracellular portion of transmembrane helix (TM) 6 by 6.8 Å as compared to the apo state (Figure 2C), and by 5.1 Å as compared to the ET-1-bound crystal structure (Figure 2D). The observed TM6 opening is smaller than those in other G i -coupled receptors (e.g., μOR: 10 Å, CB 1 : 11.6 Å, and S1P 1 : 9 Å) 30,32,33 .…”

Section: Resultsmentioning

confidence: 57%

“…The D 3.49 R 3.50 Y 3.51 motif is conserved in the ET B receptor. Upon receptor activation, the ionic lock between D198 3.49 and R199 3.50 is broken, and R199 3.50 becomes oriented toward the intracellular cavity (Figure 2E), as in other GPCRs 32,34–38 (Figure 2F, G). In contrast, the N 7.49 P 7.50 xxY 7.53 motif is altered to N 7.49 P 7.50 xxL 7.53 Y 7.54 , in which Y 7.53 is replaced by L386 7.53 .…”

Section: Resultsmentioning

confidence: 83%

“…These interactions are not observed in other GPCR-Gi complexes (Figure 3-figure supplement 2) 30,32,33,43 , and are unique to the ETB-Gi interface. This feature in TM7 allows the α5-helix of ETB-Gi to become located in the shallowest position relative to the receptor, among the Gs, Gi, and Gq-coupled GPCR structures 25,30,[32][33][34]43 (Figure 3B). However, the Gαi structure adopts a nucleic acid-free state, as in the μOR-Gi complex (Figure 3-figure supplement 1) 32,44 .…”

Section: Shallow G I Couplingmentioning

confidence: 79%

“…Previous structural studies have shown that the docking of the α5-helix to the receptor cavity destabilizes the nucleic acid binding site at the root of the α5-helix (Figure 3-figure supplement 1) 32,34,45 , thus promoting the GDP/GTP exchange reaction. Whereas the Gαs binding is essentially similar in all of the complexes, the Gαi binding is variable, with different Gα rotations relative to the receptor 46 .…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, R199 3.50 forms a hydrogen bond with the backbone carbonyl of C351 G.H5. 23 (superscript indicates the common Gα numbering [CGN] system 42 ), as commonly observed in other GPCR-Gi complexes 30,32,33,43 . Moreover, the C-terminal carboxylate of α5-helix forms electrostatic interactions with the backbone nitrogen atom of R391 8.48 .…”

Section: Shallow G I Couplingmentioning

confidence: 99%

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Cryo-EM structure of the endothelin-1-ET_B-G_icomplex

Sano

Akasaka

Shihoya

et al. 2023

Preprint

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The endothelin ETB receptor is a promiscuous G-protein coupled receptor, activated by vasoactive peptide endothelins. ETB signaling induces reactive astrocytes in the brain and vasorelaxation in vascular smooth muscle, and thus ETB agonists are expected to be utilized for neuroprotection and improved anti-tumor drug delivery. Here, we report a cryo-electron microscopy structure of the endothelin-1-ETB-Gi complex at 2.9-Å resolution, with complex assembly stabilized by a newly established method. Comparisons with the inactive ETB receptor structures revealed how endothelin-1 activates the ETB receptor. The NPxxY motif, which is essential for Gprotein activation, is not conserved in ETB, resulting in a unique structural change upon G-protein activation. As Compared with other GPCR-G-protein complexes, ETB binds Gi at the shallowest position, thus expanding the diversity of G-protein binding. This structural information will facilitate the elucidation of G-protein activation and the rational design of ETB-agonists.

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Section: Resultsmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 83%

Section: Shallow G I Couplingmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Shallow G I Couplingmentioning

confidence: 99%

See 3 more Smart Citations

Cryo-EM structure of the endothelin-1-ET_B-G_icomplex

Sano

Akasaka

Shihoya

et al. 2023

Preprint

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Photo‐affinity and Metabolic Labeling Probes Based on the Opioid Alkaloids

Duque,

Vallavoju,

Zhang

et al. 2024

ChemBioChem

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The opioids are powerful analgesics but carry many contingencies that can lead to opioid‐use disorder. Chemical probes derived from the opioid alkaloids can provide deeper insight into the molecular interactions in a cellular context. Here, we designed and developed photo‐click morphine (PCM‐2) as a photo‐affinity probe based on morphine and dialkynyl‐acetyl morphine (DAAM) as a metabolic acetate reporter based on heroin. Application of these probes to SH‐SY5Y, HEK293T, and U2OS cells revealed that PCM‐2 and DAAM primarily localize to the lysosome amongst other locations inside the cell by confocal microscopy and chemical proteomics. Interaction site identification by mass spectrometry revealed the mitochondrial phosphate carrier protein, solute carrier family 25 member 3, SLC25A3, and histone H2B as acylation targets of DAAM. These data illustrate the utility of chemical probes to measure localization and protein interactions in a cellular context and will inform the design of probes based on the opioids in the future.

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Towards Multitargeted Ligands as Pain Therapeutics: Dual Ligands of the Ca_vα2δ‐1 Subunit of Voltage‐Gated Calcium Channel and the μ‐Opioid Receptor

Wegert,

Monnee,

de Graaf

et al. 2024

ChemMedChem

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The synthesis and pharmacological activity of a new series of dual ligands combining activities towards the α2δ‐1 subunit of voltage‐gated calcium channels (Cavα2δ‐1) and the μ‐opioid receptor (MOR) as novel pain therapeutics are reported. A careful exploration of the pharmacophores related to both targets, which in principle had few common characteristics, led to the design of novel compounds exhibiting both activities. The construction of the dual ligands started from published Cavα2δ‐1 ligands, onto which MOR ligand pharmacophoric elements were added. This exercise led to new amino‐acidic substances with good affinities on both targets as well as good metabolic and physicochemical profiles and low potential for drug‐drug interactions. A representative compound, (2S,4S)‐4‐(4‐chloro‐3‐(((cis)‐4‐(dimethylamino)‐4‐phenylcyclohexyl)methyl)‐5‐fluorophenoxy)pyrrolidine‐2‐carboxylic acid, displayed promising analgesic activities in several in vivo pain models as well as a reduced side‐effect profile in relation to morphine.

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Molecular recognition of morphine and fentanyl by the human μ-opioid receptor

Cited by 123 publications

References 84 publications

Cryo-EM structure of the endothelin-1-ET_B-G_icomplex

Cryo-EM structure of the endothelin-1-ET_B-G_icomplex

Photo‐affinity and Metabolic Labeling Probes Based on the Opioid Alkaloids

Towards Multitargeted Ligands as Pain Therapeutics: Dual Ligands of the Ca_vα2δ‐1 Subunit of Voltage‐Gated Calcium Channel and the μ‐Opioid Receptor

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Molecular recognition of morphine and fentanyl by the human μ-opioid receptor

Cited by 123 publications

References 84 publications

Cryo-EM structure of the endothelin-1-ETB-Gicomplex

Cryo-EM structure of the endothelin-1-ETB-Gicomplex

Photo‐affinity and Metabolic Labeling Probes Based on the Opioid Alkaloids

Towards Multitargeted Ligands as Pain Therapeutics: Dual Ligands of the Cavα2δ‐1 Subunit of Voltage‐Gated Calcium Channel and the μ‐Opioid Receptor

Contact Info

Product

Resources

About

Cryo-EM structure of the endothelin-1-ET_B-G_icomplex

Cryo-EM structure of the endothelin-1-ET_B-G_icomplex

Towards Multitargeted Ligands as Pain Therapeutics: Dual Ligands of the Ca_vα2δ‐1 Subunit of Voltage‐Gated Calcium Channel and the μ‐Opioid Receptor