Abstract
Despite considerable advances over the past years in understanding the mechanisms of action and the role of the σ1 receptor, several questions regarding this receptor remain unanswered. This receptor has been identified as a useful target for the treatment of a diverse range of diseases, from various central nervous system disorders to cancer. The recently solved issue of the crystal structure of the σ1 receptor has made elucidating the structure–activity relationship feasible. The interaction of seven representative opioid ligands with the crystal structure of the σ1 receptor (PDB ID: 5HK1) was simulated for the first time using molecular dynamics (MD). Analysis of the MD trajectories has provided the receptor–ligand interaction fingerprints, combining information on the crucial receptor residues and frequency of the residue–ligand contacts. The contact frequencies and the contact maps suggest that for all studied ligands, the hydrophilic (hydrogen bonding) interactions with Glu172 are an important factor for the ligands’ affinities toward the σ1 receptor. However, the hydrophobic interactions with Tyr120, Val162, Leu105, and Ile124 also significantly contribute to the ligand–receptor interplay and, in particular, differentiate the action of the agonistic morphine from the antagonistic haloperidol.
Highlights
IntroductionTwo high-resolution crystal structures of the human transmembrane σ1 receptor in complex with two ligands (a high-affinity antagonist PD144418 and either agonist or inverse agonist 4-IBP; PDB ID: The crystal data show a triangular structure constituted of three associated units with a single transmembrane domain for each protomer (Figure 1) located at the N-terminus [1]
The growing number of crystal structures of the receptors has shed a strong light on their structural features, the arrangement of the transmembrane helices, ligand–binding interactions, and specificities.Very recently, two high-resolution crystal structures of the human transmembrane σ1 receptor in complex with two ligands (a high-affinity antagonist PD144418 and either agonist or inverse agonist 4-IBP; PDB ID: The crystal data show a triangular structure constituted of three associated units with a single transmembrane domain for each protomer (Figure 1) located at the N-terminus [1]
We present and discuss the results of the molecular dynamics simulations of the σ1 receptor–ligand system based on the σ1 receptor crystal structure [1]
Summary
Two high-resolution crystal structures of the human transmembrane σ1 receptor in complex with two ligands (a high-affinity antagonist PD144418 and either agonist or inverse agonist 4-IBP; PDB ID: The crystal data show a triangular structure constituted of three associated units with a single transmembrane domain for each protomer (Figure 1) located at the N-terminus [1]. The σ1 receptor plays a role in blocking the neurodegeneration caused by β-amyloid (Alzheimer’s disease) and in inhibiting tumor-cell proliferation and has potential in many other therapies [2,3,4,5,6,7,8,9]. This receptor has been characterized as a chaperone protein, which assists in the correct folding of some other proteins [7]
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