Dataset Information

Human ? Opioid Receptor Models with Evaluation of the Accuracy Using the Crystal Structure of the Murine ? Opioid Receptor.

ABSTRACT: Models of the human ? opioid receptor were constructed using available G-protein-coupled receptor (GPCR) structures using homology (comparative) modeling techniques. The recent publication of a high-resolution crystal structure of a construct based on the murine ? opioid receptor offers a unique opportunity to evaluate the reliability of the homology models and test the relevance of introducing more templates (known structures) to increase the accuracy of the comparative models. In the first model two templates were used: the ?2 adrenergic and bovine rhodopsin receptors. For the second model, four templates were utilized: the ?2 adrenergic, bovine rhodopsin, ?1 adrenergic, and A2A adenosine receptors. Including additional templates improved the accuracy of structural motifs and other features of the model when the same sequence alignment was used. The predicted structures were especially relevant in the case of important receptor regions such as the DRY motif, which has been associated with receptor activation. Additionally, this study showed that receptor sequence similarity is crucial in homology modeling, as indicated in the case of the highly diverse EC2 loop. This study demonstrates the reliability of the homology modeling technique in the case of the ? opioid receptor, a member of the rhodopsin-like family class of GPCRs. The addition of more templates improved the accuracy of the model. The findings regarding the modeling has significant implication to other GPCRs where the crystal structure is still unknown and suggest that homology modeling techniques can provide high quality structural models for interpreting experimental findings and formulating structurally based hypotheses regarding the activity of these important receptors.

SUBMITTER: Perez-Aguilar JM

PROVIDER: S-EPMC3920553 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Human μ Opioid Receptor Models with Evaluation of the Accuracy Using the Crystal Structure of the Murine μ Opioid Receptor.

Perez-Aguilar Jose Manuel JM Saven Jeffery G JG Liu Renyu R

Journal of anesthesia & clinical research 20120701 6

Models of the human μ opioid receptor were constructed using available G-protein-coupled receptor (GPCR) structures using homology (comparative) modeling techniques. The recent publication of a high-resolution crystal structure of a construct based on the murine μ opioid receptor offers a unique opportunity to evaluate the reliability of the homology models and test the relevance of introducing more templates (known structures) to increase the accuracy of the comparative models. In the first mod ...[more]

PMID: 24527268

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Project description:BackgroundThe first crystal structure of the active μ opioid receptor (μOR) exhibited several unexplained features. The ligand BU72 exhibited many extreme deviations from ideal geometry, along with unexplained electron density. I previously showed that inverting the benzylic configuration resolved these problems, establishing revised stereochemistry of BU72 and its analog BU74. However, another problem remains unresolved: additional unexplained electron density contacts both BU72 and a histidine residue in the N-terminus, revealing the presence of an as-yet unidentified atom.ResultsThese short contacts and uninterrupted density are inconsistent with non-covalent interactions. Therefore, BU72 and μOR form a covalent adduct, rather than representing two separate entities as in the original model. A subsequently proposed magnesium complex is inconsistent with multiple lines of evidence. However, oxygen fits the unexplained density well. While the structure I propose is tentative, similar adducts have been reported previously in the presence of reactive oxygen species. Moreover, known sources of reactive oxygen species were present: HEPES buffer, nickel ions, and a sequence motif that forms redox-active nickel complexes. This motif contacts the unexplained density. The adduct exhibits severe strain, and the tethered N-terminus forms contacts with adjacent residues. These forces, along with the nanobody used as a G protein substitute, would be expected to influence the receptor conformation. Consistent with this, the intracellular end of the structure differs markedly from subsequent structures of active μOR bound to Gi protein.ConclusionsLater Gi-bound structures are likely to be more accurate templates for ligand docking and modelling of active G protein-bound μOR. The possibility of reactions like this should be considered in the choice of protein truncation sites and purification conditions, and in the interpretation of excess or unexplained density.

Dataset Information

Human ? Opioid Receptor Models with Evaluation of the Accuracy Using the Crystal Structure of the Murine ? Opioid Receptor.

Publications

Human μ Opioid Receptor Models with Evaluation of the Accuracy Using the Crystal Structure of the Murine μ Opioid Receptor.

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