The sigma-1 receptor is an endoplasmic reticulum (ER) integral membrane protein receptor is implicated in neurodegeneration, drug addiction, pain, amnesia, depression, Alzeimer’s disease, stroke, retinal neural degeneration, HIV infection, and cancer. In addition to its endogenous ligands, N,N- dimethyltryptamine (DMT) and the ER chaperone BIP, the sigma receptor binds a wide range of exogenous ligands and therapeutic compounds. Recent studies demonstrated potent antiapoptotic actions of Sigma-1, blocking neurodegeneration caused by beta-amyloid or ischemia. Other studies have shown sigma-1 antagonists capable of inhibiting tumor-cell proliferation. Despite numerous drug interactions, very little structural information about the sigma-1 receptor is available, partly because it does not share sequence homology with any other mammalian protein.
Using a specially adapted E.coli expression system we can produce large amounts of pure, functionally active and isotopically labelled sigma receptor.
We propose to solve the 3D structure of Sigma-1 by solution state NMR and characterise its ligand interactions at an atomic level and their regulation by cholesterol and ion binding. With a novel mammalian cell expression and isotopic labelling strategy and in-vivo assays we intend to further validate our work in-vivo with the aim of feeding our findings into the understanding of the Sigma-1 function in the cell and its modulation by drug binding.
The implication of sigma-1 in many diseases makes it a potentially fruitful target for therapeutic intervention. Characterisation of sigma-1 receptor structure in the absence and presence of endogenous and exogenous ligands and cholesterol will shed light on its molecular action and will allow interdisciplinary projects for the development of more efficient therapies
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