Title:	Structural studies of membrane proteins and protein complexes involved in diseases
DNr:	SNIC 2018/3-410
Project Type:	SNIC Medium Compute
Principal Investigator:	Jesper Haeggstrom <Jesper.Haeggstrom@ki.se>
Affiliation:	Karolinska Institutet
Duration:	2018-09-06 – 2019-10-01
Classification:	30401 30108
Homepage:	https://ki.se/en/mbb/jesper-haeggstrom-group
Keywords:

Abstract

The discovery of the new generation of sensitive direct-electron detectors has broadened the possibilities to determine the high-resolution structures of membrane proteins and protein complexes by Cryo-EM. Cryo-EM is now used to generate very good structural models of membrane protein complexes (Kühlbrandt, 2014). It is considered one the best reliable alternative tool to collect high-resolution structural data of membrane protein complexes with sizes above 100 KDa through 3-D reconstruction. It is possible to study the protein targets of the projects in our research group by Cryo-EM as most of their sizes are above 150 kDa. We are planning to collect and process cryo-EM data of three to five protein complexes in different projects that will require a lot more computational power and memories to run all the Cryo-EM packages simultaneously. The new single particle Cryo-EM projects will include a variety of individual projects throughout the year. This also requires several available Cryo-EM software packages that help to process the data from the simple Cryo-EM micrograph images to the final 3D reconstruction. Also, calculating structures using Cryo-EM requires high-performance computing power. As an example one of our main projects aims to understand in depth some of the key molecular mechanisms involved in the lipoxygenase pathways, the pure complexes CLP/5LO/FLAP/LTC4S or CLP/5LO/FLAP/ will be used for biochemical and structural analysis using either crystallography or Cryo-EM using the Cryo-EM facilities at SciLifeLab Our study also involved the understanding of the structural dynamics with computational analysis ((Brock et al, 2016), the processing of crystallographic data as well as electron microscopic data. The resources provided by the SNAC is the perfect platform for us to efficiently establish the relation structure-function that will guide us toward the discovery of novel pharmaceutical therapy of diseases linked to the leukotriene formation and their activities. We also aim to structurally study the association of G-proteins with BLT1R, BLT2R, CysLT1R, CysLT2R, OXER1, and FPR2 G-PCRs in their active form with their respective agonists. In addition, we are also working on dissecting out the structure of membrane proteins from the Malarial parasite, Plasmodium falciparum. In recent years we have started atoms molecular dynamics simulations (MD) studies and we are now going to use Cryo-Electron Microscopy (Cryo-EM) analysis to tackle our present scientific questions