Community Research and Development Information Service - CORDIS


SIGMA1R — Result In Brief

Project ID: 331219
Funded under: FP7-PEOPLE
Country: United Kingdom
Domain: Health, Fundamental Research

Structural analysis of receptors implicated in neurodegeneration

Cells respond to extracellular stress and damage often by evoking specific cellular processes. Understanding how these processes function in health and disease requires structural information on their components.
Structural analysis of receptors implicated in neurodegeneration
The unfolded protein response is an adaptive mechanism triggered by the accumulation of misfolded or unfolded protein species. It involves the endoplasmic reticulum (ER), the cellular site of protein and lipid synthesis.

The sigma-1 receptor (S1R) is a chaperone protein present in the membrane of the ER. Emerging evidence indicates its involvement in various diverse conditions such as neurodegeneration, HIV infection and cancer. Recent studies have underscored the potent anti-apoptotic action of S1R in blocking neurodegeneration and in inhibiting tumour cell proliferation. However, despite the interaction of the S1R with various drugs, very little structural information is currently available.

Since the S1R doesn't have any sequence homology with any other mammalian protein, scientists of the EU-funded SIGMA1R (Structural basis of sigma-1 receptor ligand interactions) project set out to characterise its 3D structure by solution-state nuclear magnetic resonance (NMR). Additionally, they aimed to characterise the ligand interactions of the receptor at the atomic level and their regulation by cholesterol and ion binding.

Researchers successfully expressed and purified the full length S1R in detergent micelles with different isotopic labelling schemes. They discovered that S1R bound various drugs with high affinity and interacted with the ER chaperone BiP. In addition, biophysical characterisation of S1R showed that it coexisted in a mixture of oligomeric states in solution. NMR mapping enabled identification of the residues at the atomic level that were affected by drug binding. Further studies into the cellular distribution of S1R provided important insight into the dynamics of the receptor in the ER and its interaction with other proteins.

Collectively, the generated information is crucial for the effective design of therapeutic drugs against neurological diseases where S1R is involved. This is particularly important since there are currently different small molecules targeting S1R in clinical trials for the treatment of neurodegeneration and neuropathic pain.

Related information


Neurodegeneration, unfolded protein, endoplasmic reticulum, sigma-1 receptor, SIGMA1R
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