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.

Public Health Relevance

(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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM119185-02
Application #
9536898
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Koduri, Sailaja
Project Start
2017-08-15
Project End
2021-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Biochemistry
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
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