Oligomerization of rhodopsin and other G-protein-coupled receptors (GPCRs)
G-protein-coupled receptors (GPCRs) constitute a large superfamily of receptor proteins responsible for signal transduction (about 800 types). These receptors mediate recognition of environmental stimuli like light, odor, and taste, but also involve responses to peptides, hormones, proteases, chemokines and other ligands across plasma membranes. They are also important targets for pharmacological intervention via activating or blocking their action. The current state of research is that GPCRs exist and act as dimers. However, a couple of years ago the monomeric state of GPCR was commonly accepted and a few cases of dimerization (like GABAB receptors) were treated as an exception. Gradually, due to growing evidence of experimental data the hypothesis of dimerization became a dominant one.
Based on distances between rhodopsin monomers, measured by Atomic Force Microscopy (AFM), we built a model of rhodopsin oligomer. The model was subsequently enhanced by simulation in membranes specific to native rod outer segment (ROS) discs. Such membranes contain unsaturated lipids (docosahexaenoyl chains) in high concentrations. Our model of rhodopsin oligomer (1N3M in Protein Data Base) was experimentally confirmed not only for rhodopsin but also for dopamine receptor. It can suggest that functional dimers of GPCRs may employ similar interfaces as well as mechanisms of signal transduction.
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A development of cryo-EM (cryo-electron microscopy) was the subject of the Nobel Prize in Chemistry 2017. Recently, this method became so precise that it is possible to obtain the structures of large biomolecular complexes with very high, atomic resolution. This article [»»»] describes in short the cryo-EM method and the Nobel laureates (including YouTube movie).
Currently, our group works on the γ-secretase, the very large complex of 4 membrane proteins. This complex produces β-amyloid being a hallmark of Alzheimer's disease. The determination of structure of this complex was possible only using the cryo-EM method.
We revealed how the hydrophobic ligands entry to and exit from CB1 cannabinoid receptor directly from the membrane, Published in J. Chem. Inf. Model. (2016) (DOI).
New papers linking the activation of GPCRs with water flows inside receptor: in Nature Communication (2014) (DOI) and in Angew. Chem. Int. Ed. (2015) (DOI).
The web server GPCRM, built by BIOmodeling group for construction of homology models of GPCRs based on multiple templates, proved to be one of the best among other services of this type so it was recently selected to be implemented into GPCRDB platform. Employing this service we participated in GPCR Dock competition for docking of ligands to unknown structures of serotonin receptors 5-HT1B and 5-HT2B where we obtained 2nd and 1st place, respectively.
The Nobel prize in Chemistry for 2013 was awarded to three computer scientists. They created foundations of methods for molecular modeling and molecular dynamics to study both small molecules and large systems composed of DNA and proteins enabling docking of ligands to molecular targets for drug design. They developed a concept of force-field and also combined these methods with quantum chemistry to simulate enzymatic reactions.