The rockefeller university

A ubiquitous family of cell-surface receptors called G protein-coupled receptors act as transducers for myriad processes, ranging from color vision to hormone signaling to synaptic transmission. These receptors are also the targets for approximately one-third of therapeutic drugs. The Sakmar laboratory examines the molecular mechanisms by which G protein-coupled receptors work and develops new technologies to advance drug discovery targeting cancer, inflammation, and autoimmune disorders.

The primary research focus of the Sakmar laboratory is to study the biology and chemistry of heptahelical G protein-coupled receptors (GPCRs). The mechanism of transmembrane signaling by heptahelical receptors is an area of intense scientific interest that has tremendous biological and pharmaceutical relevance.

The laboratory has pioneered novel methods, including genetic code expansion to introduce unnatural amino acids into expressed receptors, as a tool for GPCR-targeted drug discovery. The researchers recently adopted a variety of ancillary experimental approaches, including targeted photocrosslinking to map ligand and antibody binding sites; bioorthogonal labeling reactions to introduce site-specific fluorophores; and monoclonal antibody epitopes to facilitate single molecule imaging studies. These strategies can be combined with traditional approaches to study GPCRs, channels, and other difficult-to-express membrane proteins.

Sakmar’s work has focused primarily on family A GPCRs, also known as the rhodopsin family, 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 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 crosstalk between signaling pathways. In addition, the lab has studied how mutations in genes encoding GPCRs result in expressed receptors with high levels of basal activity. One such gene, CYSLTR2, causes a rare ocular cancer called uveal melanoma, and is the first known example of a GPCR “driver” oncogene.

Proteomics approaches to elucidate the roles of accessory regulatory proteins that interact with GPCRs are also under study. This work uses novel suspension bead array assays facilitated to engineering GPCR expression libraries and curated antibodies from the Human Protein Atlas.

A new area of research in the Sakmar lab focuses on human protein folding disorders and amyloidosis syndromes. The lab has discovered novel chaperone-like amyloid-binding proteins that can be engineered to stabilize transient amyloid intermediates and create unique panels of monoclonal antibodies with diagnostic or therapeutic potential.

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.