Alzheimer's Disease - structure of gamma-secretase complex
Presenilin-1 (PS-1) is a catalytic component of the membranous complex of γ-secretase which plays an important role in onset and development of Alzheimer’s Disease. It cuts the APP (Amyloid Precursor Protein) to β-amyloid which can aggregate in neurons. The γ-secretase complex consists of four proteins: PS1, APH-1, PEN-2 and nicastrin (Nct). Structures of all of these proteins are unknown. In the maturation process the structure of PS-1 is cleaved on N- and C-terminal fragments (NTF and CTF). Structure of CTF was determined using NMR methods in detergent micelles (Sobhanifar et al., PNAS 2010). Our group revealed how this structure is changing in a micelle of detergent molecules as well as in lipid bilayers (DLPC, DPPC and implicit) using different types of molecular dynamics simulations. This research is continued toward determination of interactions with the substrate APP and drug design.
(Cooperation with BioNMR Centre at Goethe University, Frankfurt/Main, Germany)
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.