B.S., M.S., Bucknell University, 1974; Ph.D., Princeton University, 1978. Assistant Professor, Caltech, 1979-85; Associate Professor, 1985-89; Professor, 1989-2001; Hoag Professor, 2002-. Executive Officer for Chemistry, 1994-99.

Organic, Physical Organic, Bioorganic, and Materials Chemistry Assistant: Linda Syme The Dougherty group in the Division of Chemistry and Chemical Engineering at the California Institute of Technology conducts research in organic chemistry and chemical biology. The major focus of the group seeks a chemical-scale understanding of ion channels and neuroreceptors. These integral membrane proteins are the molecules of memory, learning, and sensory perception. They are also the targets of pharmaceuticals intended to treat Alzheimers disease, Parkinsons disease, schizophrenia, learning and attention deficits, and many others disorders. By using a combination of organic synthesis, molecular biology, electrophysiology, and computer modeling, detailed structural and mechanistic insights into these complex systems can be obtained. Ion channels are also the ultimate molecular sensors. These proteins transduce a chemical event - binding of a small organic molecule - into an electrical signal (flow of ions). The sensitivity of modern electronics allows single molecule detection to be routinely achieved. As such, another goal of the group is to use ion channels as a platform for developing novel signaling/sensing systems. We also have a long-standing interest in fundamental aspects of biological recognition, and have extensively studied the cation-p interaction as an important general force in structural biology. We continue to evaluate new systems that provide examples of this important and broadly general noncovalent binding interaction.

Biochemistry and Molecular Biophysics; Chemistry

Allosteric activation of the 5-HT3AB receptor by mCPBG, T.F. Miles, H.A. Lester, D.A. Dougherty, Neuropharm., 2014, pii: S0028-3908(14)00469-9. DOI: 10.1016/j.neuropharm.2014.12.018

Structural Requirements in the Transmembrane Domain of GLIC Revealed by Incorporation of Noncanonical Histidine Analogs, M. Rienzo, S.C. Lummis, D.A. Dougherty, ACS Chem Biol., 2014, 21, 1700-6. DOI: 10.1016/j.chembiol.2014.10.019

Functional Evaluation of Key Interactions Evident in the Structure of the Eukaryotic Cys-Loop Receptor GluCl, K.N. Daeffler, H.A. Lester, D.A. Dougherty, ACS Chem Biol., 2014, 9, 2283-90. DOI: 10.1021/cb500323d

In vivo incorporation of non-canonical amino acids by using the chemical aminoacylation strategy: a broadly applicable mechanistic tool, D.A. Dougherty, E.B. Van Arnam, Chembiochem., 2014, 15, 1710-20 DOI: 10.1002/cbic.201402080

Subtype-specific mechanisms for functional interaction between α6β4* nicotinic acetylcholine receptors and P2X receptors, W. Limapichat, D.A. Dougherty, H.A. Lester, Mol Pharmacol., 2014, 86, 263-74. DOI: 10.1124/mol.114.093179

Functional probes of drug-receptor interactions implicated by structural studies: Cys-loop receptors provide a fertile testing ground, E.B. Van Arnam, D.A. Dougherty, J Med Chem., 2014, 57, 6289-300. DOI: 10.1021/jm500023m

Selective ligand behaviors provide new insights into agonist activation of nicotinic acetylcholine receptors, C.B. Marotta, I. Rreza, H.A. Lester, D.A. Dougherty, ACS Chem Biol., 2014, 9, 1153-9. DOI: 10.1021/cb400937d

Probing the Non-Canonical Interface for Agonist Interaction with an α5 Containing Nicotinic Acetylcholine Receptor, C.B. Marotta, C.N. Dilworth, H.A. Lester, D.A. Dougherty, Neuropharm., 2013, 77, 342-349. DOI: 10.1016/j.neuropharm.2013.09.028

The 5-HT3AB receptor shows an A3B2 stoichiometry at the plasma membrane, T. F. Miles, D. A. Dougherty, and H. A. Lester, Biophys. J., 2013, 105, 887-898. DOI: 10.1016/j.bpj.2013.07.015

An unusual pattern of ligand-receptor interactions for the α7 nicotinic acetylcholine receptor, with implications for the binding of varenicline, E. B. Van Arnam, E. E. Blythe, H. A. Lester, and D. A. Dougherty, Mol. Pharm., 2013, 84, 201-207. PMCID: PMC3716316

Binding Interactions To The Complementary Subunit Of Nicotinic Receptors A. P. Blum, E. B. Van Arnam, L. A. German, H. A. Lester, and D. A. Dougherty, J. Biol. Chem., 2013, 288, 6991-6997. PMCID: PMC3591609

The Cation-π Interaction, D. A. Dougherty, Accts. Chem. Res., 2013, 46, 885-893. dx.doi.org/10.1021/ar300265y

Key Binding Interactions for Memantine in the NMDA Receptor, W. Limapichat, W. Yu, E. Branigan, H. A. Lester, D. A. Dougherty, ACS Chem. Neurosci., 2013, 4, 255-260. doi.org/10.1021/cn300180a.

GABA Binding to an Insect GABA Receptor: A Molecular Dynamics and Mutagenesis Study, J. A. Ashby, I. V. McGonigle, K. L. Price, N. Cohen, F. Comatini, D. A. Dougherty, C. Molteni, S. C. R. Lummis, Biophys. J., 2012, 103, 2071-2081. PMCID: PMC3512037

Forster Resonance Energy Transfer (FRET) correlates of altered subunit stoichiometry in Cys-loop receptors, exemplified by nicotinic α4β2 R. Srinivasan, C. I. Richards, C. Dilworth, F. J. Moss, D. A. Dougherty, and H. A. Lester, Int. J. Mol. Sci., 2012, 13, 10022-10040. PMCID: PMC3431844

Live-Cell Imaging of Single Receptor Composition Using Zero-Mode Waveguide Nanostructures, C. Richards, K. Luong, R. Srinivasan, S. Turner, D. A. Dougherty, H. A. Lester, Nano Lett., 2012, 12, 3690-3694. PMCID: PMC3397148

Pentameric ligand-gated ion channel ELIC is activated by GABA and modulated by benzodiazepines, D. Bertrand, H. Nury, S. Lummis, D. A. Dougherty, M. Veheij, P. Legrand, J. Ramerstorfer, R. Spurny, Proc. Natl. Acad. Sci., 2012, 109, E3028-E3034. PMCID: PMC3497736

Functionally Important Aromatic-Aromatic and Sulfur-π Interactions in the D2 Dopamine Receptor, K. N. M. Daeffler, H. A. Lester, D. A. Dougherty, J. Am. Chem. Soc., 2012, 134, 14890-14896. PMCID: PMC3461201

Ondansetron and Granisetron Binding Orientation in the 5-HT3 Receptor Determined by Unnatural Amino Acid Mutagenesis, N. H. Duffy, H. A. Lester, D. A. Dougherty, ACS Chem. Biol., 2012, 7, 1738-1745. DOI: 10.1021/cb300246j. PMCID: PMC:3477246

A Coupled Array Of Noncovalent Interactions Impacts The Function Of The 5-HT3A Serotonin Receptor In An Agonist-Specific Way, T. F. Miles, K. S. Bower, H. A. Lester, D. A. Dougherty, ACS Chem. Neurosci., 2012, 3, 753-760. DOI: 10.1021/cn3000586. PMCID: PMC3474281