GPCRs under study in the Sakmar laboratory are involved in vision and taste perception, glucose metabolism, the brain’s response to dopamine and the ability of the AIDS virus to enter human cells. As a primary model for transmembrane signaling, Dr. Sakmar explores the structure and activity of light-sensing membrane proteins and their intracellular partners found in the photoreceptor cells of the retina. During his postdoctoral research training, Dr. Sakmar was among the first scientists to study the function of a newly discovered class of cellsurface receptors using techniques of molecular biology. Using rhodopsin, the receptor for dim light in the retina, Dr. Sakmar has continued to study the dynamics of receptor activation — the conformational changes that rapidly occur when rhodopsin absorbs a photon of light or a receptor binds to a hormone.

Rhodopsin’s signal transduction partner, transducin, receives signals from the membrane and relays them into the cell. Research by Dr. Sakmar and his colleagues on these two key molecules has provided insights into retinitis pigmentosa, a group of retinal degenerative disorders that affect approximately 80,000 people in the United States. This work also has clinical implications for understanding retinal and macular degeneration, night blindness, color blindness and a number of other vision disorders.

Among GPCRs, high-resolution structural information is currently available only for rhodopsin, which is a prototype of the Family A class. The Family B GPCRs, defined by long extracellular N-terminal tails, comprise receptors for up to 50 peptide hormones and include glucagon receptor, which maintains normal blood glucose levels.

Because little is known about the structural elements of Family B GPCRs that define peptide affinity and specificity, and the molecular mechanism of receptor activation, the Sakmar laboratory’s long-term objective is to elucidate the molecular mechanism of signal transduction by peptide hormone receptors. Scientists in the lab study the glucagon receptor as a model system for the Family B GPCRs, and they attempt to obtain site-specific structural information about the receptor using an interdisciplinary approach.

Additionally, computer-generated structural models of GPCRs based on the crystal structure of rhodopsin have allowed the Sakmar lab to study specific receptor-drug interactions with the aim of improving the design and synthesis of new drugs with higher potency and fewer side effects. For example, HIV, the virus that causes AIDS, hijacks a GPCR found on lymphocytes, the chemokine receptor CCR5, to gain entry into the cell. A new class of drugs designed to bind to the chemokine receptor and block HIV cellular entry is being developed using knowledge of GPCR biology. Researchers in the Sakmar laboratory are studying the structure of the chemokine receptor and how it is modified by cellular enzymes during its biosynthesis.

Finally, the Sakmar lab is interested in the human D4 dopamine receptor, a synaptic neurotransmitter receptor responsible for neuronal signaling in the mesolimbic system of the brain, a part of the brain that regulates emotion and complex behavior. It is a particularly interesting GPCR because a large number of polymorphic variants of the receptor gene exist in the human population. The gene varies in the nucleotide sequence of the region encoding the intracellular polypeptide loop that links transmembrane segments 5 and 6. The hypothesis underlying the work on the D4 receptor is that the 5-6 loop might allow it to talk to cellular adaptor proteins that feed into so-called non-canonical G protein signaling pathways.

In summary, the Sakmar laboratory takes a multidisciplinary approach — from computational chemistry to structural biology to advanced imaging methods of cell biology — to address what happens at the cell membrane during signal transduction.

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.