Research objectives in the Molecular Pharmacology Research Center focus on the G-protein coupled receptor superfamily. G-protein coupled receptors regulate a wide range of critical physiologic functions (e.g. food intake, glucose homeostasis, perception of pain) and have therefore emerged as one of the leading targets for drug discovery.
Specific efforts in the Molecular Pharmacology Research Center focus on understanding structure-function relationships, mechanisms of intracellular signal transduction and physiologic functions of G-protein coupled receptors (GPCRs).
Current investigations are aimed at (i) exploring how genetic variation in human GPCRs (i.e. single nucleotide polymorphisms) influence the development of obesity/diabetes (ii) investigating the potential of virally delivered recombinant proteins as novel therapeutics (e.g. for the treatment of movement disorders), and (iii) identifying novel compounds which mediate or block GPCR activity (i.e. drug screening/ chemical deorphaning). To accomplish these objectives, the laboratory utilizes cell-based assays, and animal models (e.g. genetically altered mice). The group is currently studying the orphan receptor, GPR88 as well as selected orexigenic and anorexigenic GPCRs (e.g. melanocortin, ghrelin, glucagon-like peptide 1, opioid).
In parallel to our studies on mammalian GPCRs, we utilize Drosophila as a model organism to pursue gene discovery and assessment of corresponding protein function. Ongoing efforts include identification of candidate modulators of feeding behavior as well as proteins which regulate neuronal/muscular physiology. Drosophila genes with conserved mammalian homologs are prioritized for study, in vitro (e.g. gene silencing in adipocyte or neuronal cell lines) and in vivo (e.g. transgenic rescue).
Research Administrator: Dionne Bradford
Research Focus and Highlights
The research interests of Martin Beinborn, MD focus on the molecular processes that lead to ligand-induced activation of peptide hormone receptors, and the downstream triggering of intracellular signaling cascades. As a model system to explore the underlying mechanisms, he has been working over the past several years on the G-protein coupled receptors (GPCRs) for the gastrointestinal hormone/neurotransmitter cholecystokinin (CCK).
Mutational analysis of recombinant CCK receptors led to the identification of two distinct yet interacting processes that determine agonist-induced receptor activation: (i) ligand-specific interactions at selected amino acids within a putative receptor transmembrane domain binding pocket, and (ii) the equilibrium set point between ‘active’ and ‘inactive’ receptor conformations. It is of note that there is evidence for multiple ‘active’ receptor conformations that may be differentially activated by a given CCK receptor ligand and that can induce in the selective stimulation of different intracellular second messenger systems (e.g., inositol phosphate formation vs. cAMP production).
More recently, Dr. Beinborn’s group has begun to explore to what extent these general principles as developed for CCK receptors (categorized as class A, rhodopsin-type GPCRs) are applicable to members of the class B subfamily of receptors (which share a seven transmembrane domain topology yet have no sequence homology with the class A proteins). The latter studies focus on the receptors for glucagon-like peptides (GLP), which are important physiological regulators of blood glucose levels, satiety, and resorption of nutrients through the intestinal mucosa.
Specific projects that are currently pursued in the Beinborn Lab include (i) to identify amino acids, both in the GLP-1 receptor and in its peptide ligands, that are triggers of second messenger signaling; (ii) to investigate compatibility of GLP-1 receptor stimulation with the ‘extended ternary model’, a molecular theory of receptor activation that has been formulated based on class A receptor function, and (iii) to explore the mechanisms underlying tonic activity of the GLP-1 receptor when this protein is expressed in the context of highly differentiated pancreatic beta cells. These studies, centered around different aspects of GLP-1 receptor function, may accelerate the discovery of novel non-peptide agonists that can mimic the function of endogenous hormone. Such compounds, given their potential to facilitate glucose-induced insulin secretion, hold considerable promise as a future pharmacotherapy of type II diabetes.
Beinborn Lab Publications
1. Point mutations in either subunit of the gabab receptor confer constitutive activity to the heterodimer. Mol Pharmacol. 2006 Jul.
2. Class B GPCRs: a hidden agonist within? Mol Pharmacol. 2006 Jul.
3. Menetrier's disease in a patient with Helicobacter pylori infection is linked to elevated glucagon-like peptide-2 activity. Scand J Gastroenterol. 2005 Apr.
4. A human glucagon-like peptide-1 receptor polymorphism results in reduced agonist responsiveness. Regul Pept. 2005 Aug.
5. Basal receptor activation by locally produced glucagon-like peptide-1 contributes to maintaining beta-cell function. Mol Endocrinol. 2005 May.
See All MCRI Publications
Alan Kopin, MD
Professor of Medicine, Tufts University School of Medicine
Alan S. Kopin is Professor of Medicine and Director of the Molecular Pharmacology Research Center at Tufts Medical Center. He is also a Professor of Pharmacology and Genetics at the Sackler School, Tufts University School of Medicine. He received his B.A. in biology from Brown University and an M.D. from the University of North Carolina School of Medicine. He is currently board certified in internal medicine and in gastroenterology. His research training included fellowships in physiology at Harvard Medical School and in gastroenterology at Tufts Medical Center. His research is focused on the study of G-protein coupled receptors, and the development of molecular tools to expedite drug discovery.
Martin Beinborn, MD
Assistant Professor of Medicine, Tufts University School of Medicine
Martin Beinborn is an Assistant Professor of Medicine at Tufts Medical Center and the Co-Director of the Molecular Pharmacology Research Center. He received his M.D. degree from Duesseldorf University, and went on to obtain postgraduate training in pharmacology at Hannover Medical School, Germany, as well as in molecular gastroenterology at Brigham and Women's Hospital / Harvard Medical School in Boston. In 1993, Dr. Beinborn was board-certified in the subspecialties of Pharmacology and Toxicology, and came to Tufts Medical Center to work with Dr. Alan Kopin on the molecular pharmacology of cholecystokinin/gastrin receptors. In addition to this ongoing collaboration, Dr. Beinborn has established a research program that focuses on the receptor for glucagon-like peptide, a potential target for the treatment of diabetes and obesity.
Ci Chen graduated form Beijing Institute of Traditional Chinese Medicine. She got her certificate of Biomedical Laboratory and Clinical Sciences from Boston University School of Medicine in 1992. Since 1997, she has worked in the laboratories of Drs. Alan Kopin and Martin Beinborn. She is involved in studies examining the molecular determinants of second messenger signaling for receptors in the CCK/gastrin and GLP families.
Jamie Doyle received her B.S. in Chemistry from Wake Forest University in 2002. She then moved to Boston and received her Ph.D. from Boston University. Jamie completed her thesis work in Pharmacology in the Neurochemistry Laboratory of Dr. Bryan Yamamoto, studying the effects of chronic stress on the toxicity of the drug of abuse methamphetamine. Dr. Doyle joined the MPRC in 2009. The focus of her research is on the characterization of G-protein coupled receptor (GPCR) variants that are associated with diabetes and obesity. The GPCRs selected for pharmacological characterization are based upon the genetic association of GPCR non-synonymous SNPs with clinical data from the Look AHEAD (Action for Health in Diabetes) study, a randomized 4 year lifestyle intervention trial of ~5,000 obese subjects with type-2 diabetes. GPCR variant characterization includes assessment of receptor affinity, potency, second messenger signaling, and expression.
Isabelle Draper, PhD
Assistant Professor of Medicine, Tufts University School of Medicine
Isabelle Reveillaud-Draper earned her Ph.D. in Biochemistry from the Université des Sciences et Techniques de Montpellier, France, in 1985, studying the structural organization of small nuclear ribonucleoproteins. She then joined Dr. Tom Kornberg's laboratory at the University of California, San Francisco, for a post-doctoral position working on developmental characterization of the Drosophila engrailed locus. From 1988 to 1992 she was a research associate at the Linus Pauling Institute of Science and Medicine in Palo Alto, CA, where she generated transgenic Drosophila for the enzyme Superoxide Dismutase, in order to assess the free radical theory of aging. There she won a grant from the American Federation for Aging Research for the development of transgenic animals for aging research. As a member of Dr. Kopin’s laboratory, she is now pursuing in vivo studies of GPCR function, using Drosophila melanogaster as a model system for understanding structure/function relationships and the physiology linked to these receptors.
Benjamin Harwood, Ph.D.
Dr. Benjamin Harwood received his B.S. in biology from Acadia University in Wolfville, Nova Scotia, Canada in 2005. He then went on to work as a research technician at the Jackson Laboratory in Bar Harbor, Maine. Ben moved to Boston and did his graduate studies in the Genetics program at Tufts University Sackler School of Graduate Biomedical Science in the laboratory of Dr. Alan Kopin. He completed his PhD. in 2014 and is now a post-doctoral fellow in the Kopin laboratory. Ben’s research focuses on rickets, an insect specific G protein-coupled receptor. Using a combination of in vitro pharmacology and model organisms (e.g. Drosophila melanogaster), he is trying to better understand the underlying biology of this receptor. In addition, Ben is developing small molecule antagonists and validating rickets as novel insecticide target.
Bina Julian, M.Eng.
Bina Julian holds a B.S. in biological engineering and a M.Eng. in biomedical engineering from Cornell University. She is currently a neuroscience graduate student under Dr. Alan Kopin in the Molecular Pharmacology Research Center at Tufts Medical Center. Bina’s current research focuses on translatable protein-based tools to characterize the role of G protein-coupled receptors in inflammation. She is also an executive committee member of the Tufts Biomedical Business Club. Prior to Tufts, Bina was a senior research associate under Dr. Todd Golub in the Cancer Program at the Broad Institute of Harvard and MIT. Bina has also held positions at Pfizer Global R&D in the Kinase Selectivity Screening platform and at Boston Biomedical Consultants in the market research areas of in vitro diagnostics and biomarkers.
Dionne Bradford joined the MCRI in June 2006 as a Research Administrator. In this role she is responsible for identifying new funding opportunities, submission of grant proposals, and all post-award including financial tracking. Additionally, Dionne works closely with the Director of Administration and Finance on matters relating to research facilities, human resources, technology transfer, and compliance issues. Prior to joining the MCRI, Dionne worked for the CBR Institute/Harvard Medical School. Dionne is an alumna of the University of Massachusetts.