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Dean R Madden, PhD

Professor of Biochemistry and Cell Biology

Additional Titles/Positions/Affiliations
Vice Provost for Research
Director, Dartmouth Institute for Biomolecular Targeting
Director, DartCF -- the Dartmouth Cystic Fibrosis Research Center

Biochemistry and Cell Biology

A.B. Physics, Harvard 1985
Ph.D. Biophysics, Harvard 1992

Academy of Master Faculty Educators
Molecular and Cellular Biology Graduate Programs
Neuroscience Center at Dartmouth
Quantitative Biomedical Sciences


Academic Analytics
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Contact Information

Dartmouth Biochemistry & Cell Biology
7200 Vail Building
Hanover NH 03755

Office: Vail 408a
Phone: 603-646-5197
Fax: 603-650-1128
Email: dean.madden@dartmouth.edu

Assistant: Cassidy Jacques
Asst. Phone: 603-646-0714
Asst. Email: cassidy.l.jacques@dartmouth.edu

Professional Interests

The goal of our research is to understand the functional characteristics of ion channels and transporters in terms of their molecular structure. Transmembrane electrochemical gradients underpin a wide variety of essential physiological processes, including photosynthesis and respiration, muscle contraction and nerve signalling. Highly specialized ion transporters are responsible for establishing and maintaining these gradients, while ion channels are designed to exploit the gradients by selectively and/or temporarily permeabilizing the membrane in response to external stimuli. Here is an overview of our research projects:

A major focus of our research involves the AMPA-receptor subfamily of glutamate receptor ion channels, which are found in the postsynaptic membrane and are responsible for most fast excitatory cell-to-cell communication in the central nervous system. After binding to neurotransmitter released from the presynaptic membrane, they open to conduct cation fluxes that depolarize the membrane and stimulate the receiving cell to fire. The channels then spontaneously close ("desensitize"). The kinetics and magnitude of the current can be fine-tuned to cellular requirements by controlling the nature and identity of the glutamate receptor subunits expressed. We wish to understand this complicated molecular machine at the atomic level. Research projects include:

Stereochemistry and thermodynamics of ligand binding:
Published crystallographic data from other groups have shown that agonist binding is associated with a Venus-flytrap style cleft closure in the glutamate receptor. How does the interaction and cleft closure proceed? To understand the exact sequence of molecular events, we have combined site-directed mutagenesis with fluorescence spectroscopy to follow the kinetics of agonist association, leading to a model in which rapid docking to one side of the open cleft is followed by cleft closure and trapping of ligand. We also use small-angle X-ray techniques to follow the conformational dynamics of the LBD in solution. Finally, we have crystallized LBD constructs from additional AMPA-R subunits, revealing additional conformational contributions to channel activation.

Molecular Architecture of AMPA-Receptors:
Although conformational changes in the LBD have been studied in great detail, little is known about how the LBD are assembled to form a molecular machine that can activate the associated ion channel. We have developed a robust expression system for the purification of intact AMPA-R and use electron microscopy to study the structure of these channels.

We are also interested in understanding binding interactions of the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride ion channel found in the lung and other epithelial tissues. CFTR mutations leading to trafficking and folding defects are the most common source of genetic disease among Caucasians. Our goal is to characterize the interaction of CFTR with binding partners that regulate trafficking and folding processes.

Design of CAL-selective inhibitors:
We have shown that CAL limits the post-maturational stability of the ΔF508-CFTR mutant, which is carried by ~90% of CF patients. Furthermore, this interaction is mediated by the CAL PDZ domain. More recently, we have demonstrated that the CAL:CFTR interaction is potentially susceptible to selective disruption. Current research is focused on the design and identification of inhibitors selective for the CAL PDZ binding site, and the evaluation of their therapeutic potential. Our work involves a combination of X-ray crystallography, NMR, fluorescence spectroscopy, high-throughput screening of small-molecule inhibitors, and electrophysiological studies of polarized epithelial cell monolayers.

Targeting Pseudomonas infections:
Due to impaired mucociliary clearance, chronic infection with Pseudomonas aeruginosa is major cause of CF morbidity. Our collaborators in the O'Toole and Stanton labs have identified Cif (CFTR Inhibitory Factor) as a Pseudomonas protein that further suppresses CFTR expression and may therefore facilitate airway colonization. We are studying the structure and function of Cif, using X-ray crystallography and enzyme-activity assays, in order to identify its physiological substrates and mechanism of action.

Understanding regulators of CFTR endocytic trafficking:
In collaboration with colleagues at the University of Pittsburgh, we are analyzing the role of proteins that interact with CFTR to control its endocytic uptake. Ultimately, these proteins may provide additional therapeutic targets.

Grant Information


Past: NIH/NIAID; CF Foundation

Courses Taught

Biochemistry 101: Molecular Information in Biological Systems

Past: Biochemistry 110: The Biochemical and Genetic Basis of Medicine

Mentoring Information

Dean mentors early-career faculty interested in small-group teaching, graduate education, and research at the interface of medicine, biology, chemistry, and math. He oversees junior faculty mentoring in the COBRE Institute for Biomolecular Targeting and leads GrantGPS -- a College-wide initiative to support faculty scholarship.


Dean started teaching math at a summer ‘bootcamp’ for MPP students, and has since taught math, biochemistry, and biophysics in Munich, Heidelberg, Cambridge, and Hanover. He served as Chair of the MCB Graduate Program and has participated in Dartmouth’s Strategic Planning for Graduate Education and the Geisel Curriculum Reform initiative, where he served as co-chair of the Biomedical Sciences Working Group and a member of the Master’s Degree Task Force. Dean is currently serving as Vice Provost for Research for Dartmouth College. He is also course director for BIOC101 – the MCB first-term core course, and PI of two program-project grants: the COBRE Institute for Biomolecular Targeting and the Dartmouth Cystic Fibrosis Research Center.

Selected Publications


Molecular basis for the transcriptional regulation of an epoxide-based virulence circuit in Pseudomonas aeruginosa.
He S, Taher NM, Hvorecny KL, Ragusa MJ, Bahl CD, Hickman AB, Dyda F, Madden DR
bioRxiv. 2024 Jan 16; pii: 2024.01.16.572601. doi: 10.1101/2024.01.16.572601. Epub 2024 Jan 16.
PMID: 38293063

Additive energetic contributions of multiple peptide positions determine the relative promiscuity of viral and human sequences for PDZ domain targets.
Tahti EF, Blount JM, Jackson SN, Gao M, Gill NP, Smith SN, Pederson NJ, Rumph SN, Struyvenberg SA, Mackley IGP, Madden DR, Amacher JF
Protein Sci. 2023 Apr;32(4):e4611. doi: 10.1002/pro.4611.
PMID: 36851847

Additive energetic contributions of multiple peptide positions determine the relative promiscuity of viral and human sequences for PDZ domain targets.
Tahti EF, Blount JM, Jackson SN, Gao M, Gill NP, Smith SN, Pederson NJ, Rumph SN, Struyvenberg SA, Mackley IGP, Madden DR, Amacher JF
bioRxiv. 2023 Jan 10; pii: 2022.12.31.522388. doi: 10.1101/2022.12.31.522388. Epub 2023 Jan 10.
PMID: 36711692

Tryptophan mutations in G3BP1 tune the stability of a cellular signaling hub by weakening transient interactions with Caprin1 and USP10.
Sheehan CT, Hampton TH, Madden DR
J Biol Chem. 2022 Dec;298(12):102552. doi: 10.1016/j.jbc.2022.102552. Epub 2022 Sep 29.
PMID: 36183834

Model Systems to Study the Chronic, Polymicrobial Infections in Cystic Fibrosis: Current Approaches and Exploring Future Directions.
O'Toole GA, Crabbe A, Kummerli R, LiPuma JJ, Bomberger JM, Davies JC, Limoli D, Phelan VV, Bliska JB, DePas WH, Dietrich LE, Hampton TH, Hunter R, Khursigara CM, Price-Whelan A, Ashare A, Cramer RA, Goldberg JB, Harrison F, Hogan DA, Henson MA, Madden DR, Mayers JR, Nadell C, Newman D, Prince A, Rivett DW, Schwartzman JD, Schultz D, Sheppard DC, Smyth AR, Spero MA, Stanton BA, Turner PE, van der Gast C, Whelan FJ, Whitaker R, Whiteson K
mBio. 2021 Oct 26;12(5):e0176321. doi: 10.1128/mBio.01763-21. Epub 2021 Sep 21.
PMID: 34544277

Biochemical and structural characterization of two cif-like epoxide hydrolases from Burkholderia cenocepacia.
Taher NM, Hvorecny KL, Burke CM, Gilman MSA, Heussler GE, Adolf-Bryfogle J, Bahl CD, O'Toole GA, Madden DR
Curr Res Struct Biol. 2021;3:72-84. doi: 10.1016/j.crstbi.2021.02.002. Epub 2021 Feb 21.
PMID: 34235487

Specificity in PDZ-peptide interaction networks: Computational analysis and review.
Amacher JF, Brooks L, Hampton TH, Madden DR
J Struct Biol X. 2020;4:100022. doi: 10.1016/j.yjsbx.2020.100022. Epub 2020 Mar 7.
PMID: 32289118

Computational Analysis of Energy Landscapes Reveals Dynamic Features That Contribute to Binding of Inhibitors to CFTR-Associated Ligand.
Holt GT, Jou JD, Gill NP, Lowegard AU, Martin JW, Madden DR, Donald BR
J Phys Chem B. 2019 Dec 12;123(49):10441-10455. doi: 10.1021/acs.jpcb.9b07278. Epub 2019 Nov 27.
PMID: 31697075

Nanobody-based binding assay for the discovery of potent inhibitors of CFTR inhibitory factor (Cif).
Vasylieva N, Kitamura S, Dong J, Barnych B, Hvorecny KL, Madden DR, Gee SJ, Wolan DW, Morisseau C, Hammock BD
Anal Chim Acta. 2019 May 30;1057:106-113. doi: 10.1016/j.aca.2018.12.060. Epub 2019 Jan 9.
PMID: 30832908

Cysteine modifiers suggest an allosteric inhibitory site on the CAL PDZ domain.
Zhao Y, Cushing PR, Smithson DC, Pellegrini M, Pletnev AA, Al-Ayyoubi S, Grassetti AV, Gerber SA, Guy RK, Madden DR
Biosci Rep. 2018 Aug 31;38(4) pii: BSR20180231. doi: 10.1042/BSR20180231. Epub 2018 Jul 6.
PMID: 29472314

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