The 5-HT2-serotonin and D2-dopamine families of receptors represent essential targets for most atypical antipsychotics as well as drugs useful in treating obesity, sleep disorders, psychosis and autistic-spectrum disorders. It is currently unknown how these drugs interact with their target receptors. Here we aim to obtain high resolution structures of 5-HT2A- and 5-HT2B- serotonin and D2- and D4-dopamine receptors with an array of small molecules. These studies are both innovative technically and conceptually by providing an unprecedented understanding of the molecular and atomic details responsible for psychoactive drug actions. Technical achievements will include the structure of LSD in complex with its key serotonin receptor targets and typical and atypical antipsychotic drugs in complex with their serotonin and dopamine receptor targets. Additionally, models which attempt to explain ligand-specific properties of biased signaling from the perspective of ligand-receptor interactions will be tested by a combination of direct structural studies, molecular modeling, docking, site-directed mutagenesis and functional studies. We anticipate that our studies will reveal key ligand-receptor interactions essential for biased signaling for serotonin and dopamine receptors. Elucidating the molecular details for such interactions provides a template for the structure-guided design of novel therapeutics.

Public Health Relevance

Roth, Bryan L PROJECT NARRATIVE (RELEVANCE) The design of new drugs to treat major mental disorders remains challenging and error-prone. This grant seeks to discover how drugs used for treating mental disorders bind to an modulate the activity of their receptor sites of action. Such information could be used to accelerate the discovery of new treatments for serious mental disorders such as schizophrenia and depression. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH112205-02
Application #
9447206
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Nadler, Laurie S
Project Start
2017-03-06
Project End
2021-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Wang, Sheng; Wacker, Daniel; Levit, Anat et al. (2017) D4 dopamine receptor high-resolution structures enable the discovery of selective agonists. Science 358:381-386
Ishchenko, Andrii; Wacker, Daniel; Kapoor, Mili et al. (2017) Structural insights into the extracellular recognition of the human serotonin 2B receptor by an antibody. Proc Natl Acad Sci U S A 114:8223-8228
Wacker, Daniel; Wang, Sheng; McCorvy, John D et al. (2017) Crystal Structure of an LSD-Bound Human Serotonin Receptor. Cell 168:377-389.e12
Wacker, Daniel; Stevens, Raymond C; Roth, Bryan L (2017) How Ligands Illuminate GPCR Molecular Pharmacology. Cell 170:414-427