The sigma-1 receptor is an enigmatic transmembrane receptor in humans that has been implicated in a variety of disease processes, including neurodegenerative disease and heart failure. Recently, the sigma receptor has been identified as a regulator of ion channel and GPCR signaling. Despite the growing recognition of the importance of this protein, very little is known regarding the molecular basis for its activity or its contribution to disease. We will study the sigma receptor using a multifaceted approach to examine structure, pharmacology, and dynamics of this important protein. Initial efforts will focus on the use of X-ray crystallography to probe receptor activation mechanism using conformationally selective antibody fragments. Complementing this work, we will explore the role of oligomerization in sigma receptor function using electron microscopy and other methods, and we will characterize the structural dynamics of the receptor by NMR spectroscopy and computational simulations. In the long term, we aim to establish a detailed molecular understanding of the sigma receptor activity and its role in human health and disease.
(RELEVANCE) The human sigma-1 receptor is an enigmatic protein implicated in a variety human diseases including amyotophic lateral sclerosis (ALS), yet little is known regarding the molecular mechanisms of its function in normal or disease physiology. This project seeks to understand sigma-1 receptor function at the molecular level, which will ultimately lead to a better understanding of this important protein and its therapeutic potential.
|Schmidt, Hayden R; Betz, Robin M; Dror, Ron O et al. (2018) Structural basis for ?1 receptor ligand recognition. Nat Struct Mol Biol 25:981-987|