Details

Autor(en) / Beteiligte

• Koussounadis, Antonis

Titel

Modelling of fish cytokines and their receptors

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

2006

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• This thesis describes a method using an object-oriented database, P/FDM, to build 3D homology models of fish β-trefoil cytokines such as Interleukin-1 (IL-1), by exploiting existing structural data from known structures of the same fold. This β-trefoil modelling procedure is based on the powerful querying capabilities of P/FDM that allow data access, navigation, and computation to be mixed freely and easily in order to formulate complex structural queries. The structural part of the database contains objects for the description of proteins, as well as β-trefoil structure-specific entities. Data are organised according to a global β-trefoil structural alignment based on superposition of the 18 core residues of the fold. Using the P/FDM β-trefoil database, the method allows the “cutting-and-pasting” of fragments from known β-trefoil structures to model loops and to use torsion angles from structurally equivalent trefoil positions to guide side chain placement. The β-trefoil modelling method was applied to model trout (Oncorhynchus mykiss) IL-1β1, IL-1β2, IL-1FX, IL-1RA, IL-18 and catshark (Scyliorhinus canicula) IL-1β cytokines, while protein models for trout IL-1R1, TGFβ1 and TNFα1 and TNFα2 were generated using Modeller. Superposition of the modelled trout IL-1 and receptor molecules to the human homologue complexes allowed their direct comparison and revealed several regions of ligand-receptor interactions. Similar to the human complex, trout IL-1RA forms more extensive interactions with receptor binding site A than site B, in contrast to IL-1β which interacts with both sites. Although there is a high level of variability in regions involved in receptor binding between fish and human homologues, the mode of binding and overall shape of the ligand-receptor complex is probably maintained, suggesting that each species has evolved its own unique interleukin-1 signalling system through ligand-receptor co-evolution.