Ĺbo Akademi University
Supervisor: Tiina Salminen
Vascular adhesion protein-1 (VAP-1) is an enzyme with both adhesive and enzymatic functions. As VAP-1 is involved in leukocyte trafficking to sites of inflammation, inhibition of the enzyme could be of great importance in chronic diseases like rheumatoid arthritis, asthma and psoriasis. It was recently discovered that Siglecs function as natural leukocyte surface substrates for VAP-1. The main aim of my PhD project is to solve the X-ray structure of VAP-1 in complex with its substrate. This would for the first time reveal the molecular interactions of VAP-1 with its counter-receptor.
Integrins are a large family of adhesion receptors that mediate cell-cell, cell-extracellular matrix and matrix-matrix adhesion. They are heterodimers comprised of an α subunit and a β subunit. The most important domain for ligand recognition is the I (inserted) domain. Upon activation the I domain undergoes conformational changes from a "closed" inactive conformation to an "open" high-affinity active state. The conformational changes that take place upon activation of the collagen-bindning α1 I domain are the main interest of my study. The aim is to solve the 3D structure of an α1 I domain in an active conformation with and without a ligand by X-ray crystallography.
Studies of the substrate specificity of VAP-1 for Siglecs, X-ray structure determination of novel inhibitors in complex with VAP-1 and structure-function relationship studies on VAP-1 are other objectives that will be included in my thesis work. Theoretical computational methods as comparative modeling, docking studies and structural analysis will be used together with experimental methods like site-specific mutagenesis, binding studies and X-ray crystallography in both projects.