The existence of oligomeric assemblies of GPCRs has been confirmed by biochemical and biophysical studies including direct AFM imaging of rhodopsin in native membranes. The question is how they work together to transduce the signal into the cell and, further on, how the oligomeric state influences all aspects of their biological function. Crystallographic structure of rhodopsin revealed that its cytoplasmic surface is too small to bind the whole trimeric G protein and accommodate all interactions predicted from crosslinking data. According to our modeling, the trimeric transducin (G protein for rhodopsin) binds to rhodopsin tetramer.
We also revealed the modes of action of agonist/antagonist sensor in opioid receptors and investigated the central molecular switch in cannabinoid receptors (opioid and cannabinoid receptors are also GPCRs). We continue investigations of influence of ligands (agonists, antagonists and inverse agonists) on the receptor structure and the action of molecular switches in GPCRs.
The latest news
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.