Dennis A. Dougherty
George Grant Hoag Professor of Chemistry, Norman Davidson Leadership Chair, Division of Chemistry and Chemical Engineering, California Institute of Technology, USA
Chemistry on the Brain: High-Precision Studies of the Nicotine Receptor
The remarkable complexity of the human brain is evident at all levels, from anatomical to cellular to molecular. The central molecules of synaptic signaling comprise a diverse array of integral membrane proteins that are resistant to most approaches to high resolution structural characterization. As such chemistry provides the most powerful tool for unraveling the structures and functions of the molecules of memory, thought, sensory perception, Alzheimer’s, Parkinson’s and schizophrenia. Using the mindset and methodologies of physical organic chemistry, and combining them with molecular biology, electrophysiology, and computer modeling, we have probed these complex membrane proteins with a precision and subtlety normally associated with small molecule studies. We have uncovered key interactions that allow agonists to bind, and that distinguish binding of natural ligands vs. substance of abuse. We have also identified a conformational switch that couples drug binding to opening ion channel, thus providing a mechanism for linking the chemical and electrical aspects of signaling in the nervous system.Dougherty is perhaps best known for development of the cation-π interaction, a novel but potent binding interaction between molecules that plays a central role in establishing protein structures and in modulating drug-receptor interactions.The fundamental nature of the interaction was established through extensive theoretical and model studies by the Dougherty group. Dougherty also established the prevalence of the cation-π interaction in biological systems, and it is now recognized to be important in a wide range biological processes, including neurotransmission, steroid biosynthesis, drug-receptor interactions, and structural biology in general.
More recently, Dougherty has addressed molecular neurobiology, developing a method for unnatural amino acid incorporation into proteins expressed in living cells, in collaboration with Professor Henry Lester at Caltech.This powerful new tool enables chemical-scale studies of the full range of ion channels and neuroreceptors that play a central role in synaptic transmission. Dougherty has used this tool to evaluate drug-receptor interactions in a range of systems, including:the nicotinic acetylcholine receptor (nAChR); the 5-HT3 serotonin receptor; the GABAA and GABAC receptors; the NMDA receptor; K+ channels; Na+ channels; and GPCRs.Mechanisms of channel gating and ion conductance have also been developed.Through these efforts, Dougherty has produced fundamental insights into drug-receptor interactions and the signaling mechanisms they can lead to.
Awards and Honorary Societies
Phi Beta Kappa
Fellow of the Alfred P. Sloan Foundation (1983-1985)
Camille and Henry Dreyfus Teacher-Scholar (1984-1989)
ASCIT Excellence in Teaching Award (1987)
AstraZeneca Excellence in Chemistry Award (1991)
Richard Badger Teaching Award (1992)
Arthur C. Cope Scholar Award (1992)
Fellow of the American Association for the Advancement of Science (1994)
Fellow of the American Academy of Arts and Sciences (1999)
ASCIT Excellence in Teaching Award (2000)
Javits Neuroscience Investigator, NIH (2004)
NASA Tech Brief Award for “Improved Ion Channel Sensor” (2008)
ACS James Flack Norris Award in Physical Organic Chemistry (2008)