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Structural Determinants for the Binding of Morphinan Agonists to the μ-Opioid Receptor.

Cong X, Campomanes P, Kless A, Schapitz I, Wagener M, Koch T, Carloni P - PLoS ONE (2015)

Bottom Line: Subtle differences between the binding modes and hydration properties of MOP and HMP emerge from the calculations.Comparison with an MD simulation of μOR covalently bound with the antagonist β-funaltrexamine hints to agonist-induced conformational changes associated with an early event of the receptor's activation: a shift of the transmembrane helix 6 relative to the transmembrane helix 3 and a consequent loss of the key R165-T279 interhelical hydrogen bond.This finding is consistent with a previous proposal suggesting that the R165-T279 hydrogen bond between these two helices indicates an inactive receptor conformation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Computational Biophysics, German Research School for Simulation Sciences GmbH, Joint venture of RWTH Aachen University and Forschungszentrum Jülich, 52425 Jülich, Germany; Computational Biomedicine section (IAS-5), Institute of Advanced Simulation (IAS), Forschungszentrum Jülich, 52425 Jülich, Germany; Computational Biomedicine section (INM-9), Institute of Neuroscience and Medicine (INM), Forschungszentrum Jülich, 52425 Jülich, Germany.

ABSTRACT
Atomistic descriptions of the μ-opioid receptor (μOR) noncovalently binding with two of its prototypical morphinan agonists, morphine (MOP) and hydromorphone (HMP), are investigated using molecular dynamics (MD) simulations. Subtle differences between the binding modes and hydration properties of MOP and HMP emerge from the calculations. Alchemical free energy perturbation calculations show qualitative agreement with in vitro experiments performed in this work: indeed, the binding free energy difference between MOP and HMP computed by forward and backward alchemical transformation is 1.2±1.1 and 0.8±0.8 kcal/mol, respectively, to be compared with 0.4±0.3 kcal/mol from experiment. Comparison with an MD simulation of μOR covalently bound with the antagonist β-funaltrexamine hints to agonist-induced conformational changes associated with an early event of the receptor's activation: a shift of the transmembrane helix 6 relative to the transmembrane helix 3 and a consequent loss of the key R165-T279 interhelical hydrogen bond. This finding is consistent with a previous proposal suggesting that the R165-T279 hydrogen bond between these two helices indicates an inactive receptor conformation.

No MeSH data available.


Related in: MedlinePlus

Molecular structures of morphine and hydromorphone.
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pone.0135998.g001: Molecular structures of morphine and hydromorphone.

Mentions: Characterizing opioid-μOR interactions may help to understand how different compounds can trigger distinct downstream responses and cause the selective activation of particular signaling and regulatory pathways. This knowledge can be in turn exploited to develop novel potent analgesics lacking some of the undesirable properties of current opioids by activating specific μOR signaling pathways. Within this perspective, here we investigate the binding determinants and energetics of two prototypical opioid agonists, morphine (MOP) and hydromorphone (HMP), to μOR. The two agonists’ functional activities at the receptor differ. The EC50 values for cAMP (G-protein mediated responses) and for β-arrestin2 (Table 1) point to 3~4-fold increase in the potency of HMP relative to MOP [17]. By contrast, the agonists’ structural features (Fig 1) and binding affinities for μOR are very similar (Table 1). In this paper, we report structural features of the two agonists’ binding modes, along with the agonist-induced conformational changes in μOR. These changes might be present in the early steps toward an active state of the receptor.


Structural Determinants for the Binding of Morphinan Agonists to the μ-Opioid Receptor.

Cong X, Campomanes P, Kless A, Schapitz I, Wagener M, Koch T, Carloni P - PLoS ONE (2015)

Molecular structures of morphine and hydromorphone.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4539194&req=5

pone.0135998.g001: Molecular structures of morphine and hydromorphone.
Mentions: Characterizing opioid-μOR interactions may help to understand how different compounds can trigger distinct downstream responses and cause the selective activation of particular signaling and regulatory pathways. This knowledge can be in turn exploited to develop novel potent analgesics lacking some of the undesirable properties of current opioids by activating specific μOR signaling pathways. Within this perspective, here we investigate the binding determinants and energetics of two prototypical opioid agonists, morphine (MOP) and hydromorphone (HMP), to μOR. The two agonists’ functional activities at the receptor differ. The EC50 values for cAMP (G-protein mediated responses) and for β-arrestin2 (Table 1) point to 3~4-fold increase in the potency of HMP relative to MOP [17]. By contrast, the agonists’ structural features (Fig 1) and binding affinities for μOR are very similar (Table 1). In this paper, we report structural features of the two agonists’ binding modes, along with the agonist-induced conformational changes in μOR. These changes might be present in the early steps toward an active state of the receptor.

Bottom Line: Subtle differences between the binding modes and hydration properties of MOP and HMP emerge from the calculations.Comparison with an MD simulation of μOR covalently bound with the antagonist β-funaltrexamine hints to agonist-induced conformational changes associated with an early event of the receptor's activation: a shift of the transmembrane helix 6 relative to the transmembrane helix 3 and a consequent loss of the key R165-T279 interhelical hydrogen bond.This finding is consistent with a previous proposal suggesting that the R165-T279 hydrogen bond between these two helices indicates an inactive receptor conformation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Computational Biophysics, German Research School for Simulation Sciences GmbH, Joint venture of RWTH Aachen University and Forschungszentrum Jülich, 52425 Jülich, Germany; Computational Biomedicine section (IAS-5), Institute of Advanced Simulation (IAS), Forschungszentrum Jülich, 52425 Jülich, Germany; Computational Biomedicine section (INM-9), Institute of Neuroscience and Medicine (INM), Forschungszentrum Jülich, 52425 Jülich, Germany.

ABSTRACT
Atomistic descriptions of the μ-opioid receptor (μOR) noncovalently binding with two of its prototypical morphinan agonists, morphine (MOP) and hydromorphone (HMP), are investigated using molecular dynamics (MD) simulations. Subtle differences between the binding modes and hydration properties of MOP and HMP emerge from the calculations. Alchemical free energy perturbation calculations show qualitative agreement with in vitro experiments performed in this work: indeed, the binding free energy difference between MOP and HMP computed by forward and backward alchemical transformation is 1.2±1.1 and 0.8±0.8 kcal/mol, respectively, to be compared with 0.4±0.3 kcal/mol from experiment. Comparison with an MD simulation of μOR covalently bound with the antagonist β-funaltrexamine hints to agonist-induced conformational changes associated with an early event of the receptor's activation: a shift of the transmembrane helix 6 relative to the transmembrane helix 3 and a consequent loss of the key R165-T279 interhelical hydrogen bond. This finding is consistent with a previous proposal suggesting that the R165-T279 hydrogen bond between these two helices indicates an inactive receptor conformation.

No MeSH data available.


Related in: MedlinePlus