Dr. GPCR Podcast

About Dr. Thomas P. Sakmar

Tom Sakmar is a physician-scientist and professor at Rockefeller University in New York. While a chemistry undergraduate student at the University of Chicago, he attended a NATO Advanced Study Institute in Les Houches, France in 1979 where he was exposed for the first time to the nascent field of membrane biophysics and intercellular communication. Instructors at the course included Marc Chabre, Harden McConnell, Richard Henderson, Martin Rodbell, Jean-Pierre Changeux, and Martin Karplus.

After medical school and clinical training at Massachusetts General Hospital, Tom joined the laboratory of H. Gobind Khorana at the Department of Chemistry at M.I.T. for postdoctoral training, where he learned gene synthesis, cDNA cloning, site-directed mutagenesis, and heterologous expression in mammalian cells. Khorana’s lab made early key contributions and developed strategies to express, reconstitute and assay engineered GPCRs using the visual pigment rhodopsin as a model system. Tom initially focused on structure-activity relationships underlying spectral tuning and identified a glutamic acid residue in rhodopsin that serves as the retinylidene Schiff base counterion. He also went on to discover a “counterion switch” in visual pigments and to develop strategies to assay receptor-G-protein interactions and activation kinetics.

After moving to Rockefeller University with a Howard Hughes Medical Institute appointment, Tom advanced a series of novel biochemical and biophysical assay platforms, including FTIR and Raman microprobe spectroscopy to study micro-quantities of expressed visual pigment mutants. This work involved active long-term collaborators, including Richard Mathies and Fritz Siebert, and contributed substantially to elucidating the physical chemistry of spectral tuning, and to a better understanding of the molecular mechanism of activation of GPCRs. Many of the conceptual advances that stemmed from this work, such as the concept of “functional micro-domains” and the “helix movement model of receptor activation” were confirmed later when crystal structures became available. Tom’s lab also pioneered the early use of computational homology modeling, molecular dynamics simulations and coarse-grain sampling approaches for membrane proteins in collaborations with Thomas Huber, Xavier Periole, and Siewert-Jan Marrink.

Tom’s lab also developed an amber codon suppression method to genetically encode unnatural amino acids into membrane proteins expressed in mammalian cell culture. The genetic code expansion strategy for unnatural amino acid mutagenesis is a key enabling technology for the field and is being used by many laboratories. Early applications included “targeted photo-crosslinking,” and more recently, the parallel development of bioorthogonal labeling strategies to couple fluorophores to expressed receptors and other membrane proteins has allowed the creation of novel sensor constructs and single-molecule detection strategies.

Recently, Tom’s lab discovered, along with Yu Chen and Ping Chi, that a mutant of CYSLTR2 is a driver oncogene in uveal melanoma, the most common eye cancer in adults. The CysLTR2 oncoprotein displays biased constitutive activity – it activates Gq/11 but does not undergo β-arrestin-mediated down-regulation.

Dr. Thomas P. Sakmar on the web

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