Once relayed into a cell’s interior, signals from the outside world elicit responses via signal transduction. A ubiquitous family of cell surface receptors called G protein coupled receptors (GPCRs) act as transducers for myriad processes, including color vision and hormone signaling, and they have proven invaluable for drug development. The Sakmar laboratory examines the molecular mechanisms by which GPCRs work.
The primary research focus of the Sakmar laboratory is to study the biology and chemistry of heptahelical GPCRs. The mechanism of signaling by heptahelical receptors is an area of intense scientific interest that has tremendous biological and pharmaceutical relevance: Heptahelical receptors represent the largest gene family in the human genome and the largest class of drug targets in the pharmaceutical industry. For the past five years, members of the Sakmar lab have been working to develop or adapt various innovative methods to establish a robust interdisciplinary approach to support the following long-term goals:
- To elucidate the basic principles that underlie ligand recognition and specificity in heptahelical receptors
- To understand the molecular mechanism of receptor activation and signaling, including the details of dynamic conformational changes required to switch a receptor from its “off” state to its “on” state
- To understand how specific receptor proteomics and posttranslational modifications such as glycosylation, acylation, phosphorylation, and tyrosine sulfation affect receptor function
- To elucidate how receptors assemble in biological membrane bilayers and how the physical and chemical properties of the membrane affect receptor biology
- To establish a basic foundation for drug discovery aimed at modulating the pharmacological activity of heptahelical receptors responsible for disease states
Dr. Sakmar’s work has focused primarily on family A (rhodopsin family) GPCRs as a model system for biophysical studies and chemokine receptors for studies of ligand recognition and proteomics. Chemokine receptors control cell migration and also act as coreceptors for HIV-1 cellular entry. Other receptors and other aspects of G protein-mediated signaling are also under investigation. In particular, the lab is studying downstream cytoplasmic components of G protein signaling pathways, with a particular interest in defining protein-protein interactions that modulate cross talk between signaling pathways.
In addition, the lab uses high throughput screening or high-content functional assays to characterize expressed mutant receptors and a variety of analytical methods to evaluate specific receptor structural heterogeneities.
Sakmar is a faculty member in the David Rockefeller Graduate Program, the Tri-Institutional M.D.-Ph.D. Program, and the Tri-Institutional Ph.D. Program in Chemical Biology.