Abstract
The µ opioid receptor (µOR), the principal target to control pain, belongs to the G protein-coupled receptors (GPCRs) family, one of the most highlighted protein families due to their importance as therapeutic targets. The conformational flexibility of GPCRs is one of their essential characteristics as they take part in ligand recognition and subsequent activation or inactivation mechanisms. It is assessed that the intrinsic mechanical properties of the µOR, more specifically its particular flexibility behavior, would facilitate the accomplishment of specific biological functions, at least in their first steps, even in the absence of a ligand or any chemical species usually present in its biological environment. The study of the mechanical properties of the µOR would thus bring some indications regarding the highly efficient ability of the µOR to transduce cellular message. We therefore investigate the intrinsic flexibility of the µOR in its apo-form using all-atom Molecular Dynamics simulations at the sub-microsecond time scale. We particularly consider the µOR embedded in a simplified membrane model without specific ions, particular lipids, such as cholesterol moieties, or any other chemical species that could affect the flexibility of the µOR. Our analyses highlighted an important local effect due to the various bendability of the helices resulting in a diversity of shape and volume sizes adopted by the µOR binding site. Such property explains why the µOR can interact with ligands presenting highly diverse structural geometry. By investigating the topology of the µOR binding site, a conformational global effect is depicted: the correlation between the motional modes of the extra- and intracellular parts of µOR on one hand, along with a clear rigidity of the central µOR domain on the other hand. Our results show how the modularity of the µOR flexibility is related to its pre-ability to activate and to present a basal activity.
Highlights
G-protein coupled receptors (GPCRs) represent the most important protein superfamily of cell surface receptors as the target of almost 50% of approved drugs in the market [1]
The 3D structure of the m opioid receptor (mOR) was built from the coordinates obtained by X-ray diffraction structure [6] that are available in the Protein Data Bank (PDB) (ID: 4DKL). mOR was crystallized at a resolution of 2.80 Awith an antagonist covalently bounded, i.e., b-funaltrexamine, water molecules, sulfate ions, chloride ions, a cholesterol molecule, a pentaethylene glycol molecule, and a 1-monooleoyl-rac-glycerol molecule
We mainly considered the Root Mean Square Deviations (RMSD), Root Mean Square Fluctuations (RMSF), angles, and dihedral angles along the receptor backbone as reported in Results
Summary
G-protein coupled receptors (GPCRs) represent the most important protein superfamily of cell surface receptors as the target of almost 50% of approved drugs in the market [1]. GPCRs consist of a bundle of seven transmembrane a-helices (H1–H7), a soluble a-helix (H8) in the intracellular domain, three extracellular loops (EL1–EL3), a N-terminal domain, and three intracellular loops (IL1–IL3) along with a C-terminal domain in the intracellular side (Fig. 1). It took seven years until the second resolved GPCR crystallographic structure [2], i.e., human b2 adrenergic receptor, appeared in literature after the first one was reported, i.e., bovine rhodopsin in 2000 [3]. Many studies have already stressed the need and importance to develop safer and more effective therapeutic ligands targeting mOR [14, 15]
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