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Bioinformatyka strukturalna białek transbłonowych

100%

Filipek S.

Kosmos

2009

vol. 58

issue 1-2

57-66

Our genome is composed of 20-30 % of membrane proteins but number of structures of these proteins known and deposited in public databases is still small. However, new achievements in experimental techniques, especially microfocusing of X-ray beam enabling diffracting of microcrystals, as well as mutagenesis leading to obtaining of thermostable mutants are real hope for quick emerging of new structures. Theoretical methods for determination of structure of membrane proteins are still in infant phases. Usage of homology modeling is limited by small number of membrane proteins which are necessary to serve as templates whereas ab-initio methods are confined to predicting of small membrane proteins or parts of larger ones only. The area which the bioinformatics is foremost in is prediction of dynamical behavior of proteins in lipid bilayer which is still mostly inaccessible to experimental methods. Full-atom as well as coarse-grain molecular dynamics methods are used to describe investigated systems in different time scales and with different accuracy.

G protein-coupled receptors - recent advances

45%

Latek D., Modzelewska A., Trzaskowski B., Palczewski K., Filipek S.

2012

vol. 59

issue 4

515-529

The years 2000 and 2007 witnessed milestones in current understanding of G protein-coupled receptor (GPCR) structural biology. In 2000 the first GPCR, bovine rhodopsin, was crystallized and the structure was solved, while in 2007 the structure of β2-adrenergic receptor, the first GPCR with diffusible ligands, was determined owing to advances in microcrystallization and an insertion of the fast-folding lysozyme into the receptor. In parallel with those crystallographic studies, the biological and biochemical characterization of GPCRs has advanced considerably because those receptors are molecular targets for many of currently used drugs. Therefore, the mechanisms of activation and signal transduction to the cell interior deduced from known GPCRs structures are of the highest importance for drug discovery. These proteins are the most diversified membrane receptors encoded by hundreds of genes in our genome. They participate in processes responsible for vision, smell, taste and neuronal transmission in response to photons or binding of ions, hormones, peptides, chemokines and other factors. Although the GPCRs share a common seven-transmembrane α-helical bundle structure their binding sites can accommodate thousands of different ligands. The ligands, including agonists, antagonists or inverse agonists change the structure of the receptor. With bound agonists they can form a complex with a suitable G protein, be phosphorylated by kinases or bind arrestin. The discovered signaling cascades invoked by arrestin independently of G proteins makes the GPCR activating scheme more complex such that a ligand acting as an antagonist for G protein signaling can also act as an agonist in arrestin-dependent signaling. Additionally, the existence of multiple ligand-dependent partial activation states as well as dimerization of GPCRs result in a 'microprocessor-like' action of these receptors rather than an 'on-off' switch as was commonly believed only a decade ago.

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1 Acta Biochimica Polonica

1 Kosmos

1 2012

1 2009

2 Filipek S.

1 Latek D.

1 Modzelewska A.

1 Palczewski K.

1 Trzaskowski B.

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Bioinformatyka strukturalna białek transbłonowych

G protein-coupled receptors - recent advances