Thesis Type:
PhD Thesis
Abstract:
The sigma-1 and sigma-2 receptors are a pair of enigmatic membrane proteins that are promising drug targets for the treatment of several conditions. Ligands targeting the sigma-1 receptor may be useful for the treatment of neuropathic pain, ischemic stroke, Alzheimer’s disease, and other neurodegenerative diseases. Ligands targeting the sigma-2 receptor hold promise for the treatment and imaging of cancer, and for the treatment of the negative symptoms of schizophrenia. Since the discovery of these receptors, myriad small molecules have been identified that bind to these receptors with high affinity. However, despite their pharmacological tractability and therapeutic potential, the basic molecular functions of the sigma receptors remain ambiguous. The work presented in this dissertation makes key advances towards understanding the molecular biology of both sigma-1 and sigma-2 receptors. In this dissertation, I describe the first crystal structures of the human sigma-1 receptor bound to five different small molecule ligands, including classical antagonist and an agonist. These structures provide a model of the sigma-1 receptor’s structure, reveal how it binds a multitude of small ligands with high (<100 nM) affinity, and suggests a structural mechanism by which agonists may differ from antagonists. Additionally, a detailed analysis of sigma-1 receptor ligand-binding kinetics provides key insights into receptor-ligand interactions. Notably, this work reveals that the association between the sigma-1 receptor and its ligands is a multi-step process that is rate limited by a conformational change in the receptor prior to ligand binding. Finally, we identified the gene that codes for the sigma-2 receptor as Tmem97, resolving a nearly 40-year old pharmacological mystery. The identification of the sigma-2 receptor as TMEM97 unities two previously independent fields of study, simultaneously providing the sigma-2 receptor field with access to modern molecular biological techniques and the TMEM97 field with a diverse collection of pharmacological tools. Collectively, the work described here represents progress towards a molecular understanding of sigma receptor function, which will be crucial to realizing the full therapeutic potential of these enigmatic receptors.
