Ligand interaction, binding site and G protein activation of the mu opioid receptor

Cui, Xu; Yeliseev, Alexei; Liu, Renyu

doi:10.1016/j.ejphar.2013.01.060

Cited by 30 publications

(31 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In particular, the study suggests 11 residues lying in close proximity to the ligands that are most likely involved in the ligand-receptor interactions. [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42].…”

Section: Resultsmentioning

confidence: 99%

A Structural Feature of the Non-Peptide Ligand Interactions with Mice Mu-Opioid Receptors

Noori

Mücksch

Urbassek³

2015

CAD

View full text Add to dashboard Cite

By binding to and activating the G-protein coupled μ-, κ- and δ-opioid receptors in the central nervous system, opiates are known to induce analgesic and sedative effects. In particular, non-peptide opioid ligands are often used in clinical applications to induce these therapeutically beneficial effects, due to their superior pharmacokinetics and bioavailability in comparison to endogenous neuropeptides. However, since opioid alkaloids are highly addictive substances, it is necessary to understand the exact mechanisms of their actions, specifically the ligand-binding properties of the target receptors, in order to safely apply opiates for therapeutic purposes. Using an in silico molecular docking approach (AutoDock Vina) combined with two-step cluster analysis, we have computationally obtained the docking scores and the ligand-binding pockets of twelve representative non-peptide nonendogenous agonists and antagonists at the crystallographically identified μ-opioid receptor. Our study predicts the existence of two main binding sites that are congruently present in all opioid receptor types. Interestingly, in terms of the agonist or antagonist properties of the substances on the receptors, the clustering analysis suggests a relationship with the position of the ligand-binding pockets, particularly its depth within the receptor structure. Furthermore, the binding affinity of the substances is directly correlated to the proximity of the binding pockets to the extracellular space. In conclusion, the results provide further insights into the structural features of the functional pharmacology of opioid receptors, suggesting the importance of the binding position of non-peptide agonists and antagonists- specifically the distance and the level of exposure to the extracellular space- to their dissociation kinetics and subsequent potency.

show abstract

Section: Resultsmentioning

confidence: 99%

A Structural Feature of the Non-Peptide Ligand Interactions with Mice Mu-Opioid Receptors

Noori

Mücksch

Urbassek³

2015

CAD

View full text Add to dashboard Cite

show abstract

“…To interpret the experimental ligand-binding data after the seven mutations were introduced, docking calculations for the ligand naltrexone using the structure of the murine MUR (4DKL) 6 were carried out using the DockingServer e) 15 as previously described 16,17 . Affinity (grid) maps of 30×30×30 Å grid points with a spacing of 0.375 Å were used for the docking calculations.…”

Section: Methodsmentioning

confidence: 99%

Characterization of a Computationally Designed Water-soluble Human μ-Opioid Receptor Variant Using Available Structural Information

et al. 2014

Self Cite

View full text Add to dashboard Cite

Background The recent X-ray crystal structure of the murine μ opioid receptor (MUR) allowed us to reengineer a previously designed water-soluble variant of the transmembrane portion of the human MUR (wsMUR-TM). Methods The new variant of water soluble MUR (wsMUR-TM_v2) was engineered based upon the murine MUR crystal structure. This novel variant was expressed in E. coli and purified. The properties of the receptor were characterized and compared with those of wsMUR-TM. Results Seven residues originally included for mutation in the design of the wsMUR-TM, were reverted to their native identities. wsMUR-TM_v2 contains 16% mutations of the total sequence. It was overexpressed and purified with high yield. Although dimers and higher oligomers were observed to form over time, the wsMUR-TM_v2 stayed predominantly monomeric at concentrations as high as 7.5 mg/ml in buffer within a 2-month period. Its secondary structure was predominantly helical and comparable with those of both the original wsMUR-TM variant and the native MUR. The binding affinity of wsMUR-TM_v2 for naltrexone (Kd ~ 70 nM) was in close agreement with that for wsMUR-TM. The helical content of wsMUR-TM_v2 decreased cooperatively with increasing temperature, and the introduction of sucrose was able to stabilize the protein. Conclusions A novel functional wsMUR-TM_v2 with only 16% mutations was successfully engineered, expressed in E. coli and purified based on information from the crystal structure of murine MUR. This not only provides a novel alternative tool for MUR studies in solution conditions, but also offers valuable information for protein engineering and structure function relationships.

show abstract

“…Much to our delight, 7 and 9 penetrate the receptor through the respective C‐ or N‐terminal domain (Figure ). Strikingly, both domains interact, amongst others (see the Supporting Information), with aspartic acid residue D147 (D149 in human homologue) that is considered to be crucial for receptor activation . This strongly supports the activation of the MOR by both domains.…”

Section: Resultsmentioning

confidence: 99%

A Blocking Group Scan Using a Spherical Organometallic Complex Identifies an Unprecedented Binding Mode with Potent Activity In Vitro and In Vivo for the Opioid Peptide Dermorphin

Strack

Bedini

Yip

et al. 2016

Chemistry A European J

View full text Add to dashboard Cite

Herein, the selective enforcement of one particular receptor-ligand interaction between specific domains of the μ-selective opioid peptide dermorphin and the μ opioid receptor is presented. For this, a blocking group scan is described which exploits the steric demand of a bis(quinolinylmethyl)amine rhenium(I) tricarbonyl complex conjugated to a number of different, strategically chosen positions of dermorphin. The prepared peptide conjugates lead to the discovery of two different binding modes: An expected N-terminal binding mode corresponds to the established view of opioid peptide binding, whereas an unexpected C-terminal binding mode is newly discovered. Surprisingly, both binding modes provide high affinity and agonistic activity at the μ opioid receptor in vitro. Furthermore, the unprecedented C-terminal binding mode shows potent dose-dependent antinociception in vivo. Finally, in silico docking studies support receptor activation by both dermorphin binding modes and suggest a biological relevance for dermorphin itself. Relevant ligand-protein interactions are similar for both binding modes, which is in line with previous protein mutation studies.

show abstract

Ligand interaction, binding site and G protein activation of the mu opioid receptor

Cited by 30 publications

References 34 publications

A Structural Feature of the Non-Peptide Ligand Interactions with Mice Mu-Opioid Receptors

A Structural Feature of the Non-Peptide Ligand Interactions with Mice Mu-Opioid Receptors

Characterization of a Computationally Designed Water-soluble Human μ-Opioid Receptor Variant Using Available Structural Information

A Blocking Group Scan Using a Spherical Organometallic Complex Identifies an Unprecedented Binding Mode with Potent Activity In Vitro and In Vivo for the Opioid Peptide Dermorphin

Contact Info

Product

Resources

About