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:

1) To elucidate the basic principles that underlie ligand recognition and specificity in heptahelical receptors

2) 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

3) To understand how specific receptor proteomics and posttranslational modifications such as glycosylation, acylation, phosphorylation and tyrosine sulfation affect receptor function

4) To elucidate how receptors assemble in biological membrane bilayers and how the physical and chemical properties of the membrane affect receptor biology

5) 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, namely visual pigments 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 nonclassical protein-protein interactions that modulate cross talk between signaling pathways.

The Sakmar laboratory now has four converging technology platforms in place that it has either developed or adapted to study heptahelical receptor chemistry and biology:

1) All atom and coarse-grain molecular dynamics simulations of GPCRs in membrane bilayers

2) Unnatural amino acid mutagenesis of GPCRs using amber codon suppression technology

3) Use of nanoscale apolipoprotein bound bilayers (NABBs) as membrane mimic support structures for GPCRs

4) Single-molecule detection of GPCRs by total internal reflection fluorescence in self-assembling oriented tethered bilayers or in NABBs using microfluidics

In addition, high throughput screening or high-content functional assays to characterize expressed mutant receptors and a variety of analytical methods are used to evaluate specific receptor structural heterogeneities. Dr. Sakmar and his colleagues believe that these new technologies and capabilities will make significant interdisciplinary work possible to advance the understanding of how heptahelical receptors really work.

CAREER

Dr. Sakmar received his A.B. in chemistry from The University of Chicago and his M.D. from Chicago’s Pritzker School of Medicine in 1982. He was then an intern and resident in internal medicine at Massachusetts General Hospital and a clinical fellow at Harvard Medical School. In 1985 Dr. Sakmar began postdoctoral research with Nobel laureate H. Gobind Khorana in the departments of biology and chemistry at the Massachusetts Institute of Technology. In 1990 he moved to Rockefeller as assistant professor and head of laboratory. He was promoted to tenured senior professor in 1998. From February 2002 to September 2003 he served as acting president of Rockefeller. He has received an Ellison Medical Foundation Senior Scholar Award for his research on age-related macular degeneration.