SBB-TP

Structural Biology and Biophysics Training Program (SBB-TP)

Research Focus

Infectious Diseases

INFECTIOUS DISEASES Antibacterial agents, Viruses incl. HIV/HepC and Proteins (Prions)

The SSB-TP has a strong program in structural biology of infectious diseases. Focco van den Akker (Biochemistry) works on structural biology and small-molecule therapeutics design related to bacterial peptidoglycan cell wall synthesis (β-lactamases). His collaborator Paul Carey (also Biochemistry), uses Raman spectroscopy/crystallography as a tool to study intermediates of β-lactamase inhibitors. Chris Dealwis (Pharmacology) works on structural biology/protein crystallography projects involving salmonella and bacillus anthracis. Mark Chance (Proteomics Center) is using mass-spectroscopy based tools to study HIV and hepatitis C virus infections. Another virus, adenovirus is studied by Phoebe Stewart (Pharmacology), using cryo-EM. Her lab is also interested in using adenovirus as a tool for therapeutic interventions. Vivien Yee (Biochemistry) employs protein crystallography and Witold Surewicz (Physiology and Biophysics) uses a range of biophysical tools to study the human prion protein and the structural basis of the conformational changes towards the infectious form of this protein.

Neurological Disease

NEUROLOGICAL DISEASES

Another major focus of the sbb-tp program faculty is to unravel the structural basis for the pathophysiology of several neurological disorders. Corey Smith’s (Physiology and Biophysics) research focusses on the synaptic peptide transmitter regulation of hormone release; for these studies he uses advanced electrophysiological techniques in combination with spectroscopy. Sudha Chakrapani (Physiology and Biophysics) works on the structural and functional aspects of ligand and voltage-gated ion channels using EPR spectroscopy, X-ray crystallography and Patch-clamp electrophysiology. Walter Boron (Physiology and Biophysics) is a pioneer in the field of intracellular pH (pHi) homeostasis, and his approach combines structural biology with molecular and cellular techniques. Mike Maguire (Pharmacology) has long-standing interests in the physiological and biochemical roles of Mg2+ and Mn2+ transport systems, and his work involves both protein structure determinations through X-ray crystallography. Vera Moiseenkova-Bell (Pharmacology) uses Cryo-EM based approaches to study ion channels that are involved in pain sensation.

Beyond this interest in channel and transporter proteins, a number of investigators are concerned with protein misfolding that leads to neurological diseases, such as Alzheimer’s. Tingwei Mu (Physiology and Biophysics) studies ion channel protein homeostasis and folding/degradation in the cell using mass spectrometry, confocal microscopy and electrophysiology. Witold Surewicz (Physiology and Biophysics) is interested in the biophysical and biochemical aspects of prion protein folding/misfolding, and some of the major techniques in his lab include EPR spectroscopy, mass spectrometry, and surface plasmon resonance.

Visual Signaling and Disease

BIOPHYSICAL BASIS OF VISUAL SIGNALING AND DISEASE

Investigations of GPCR signaling and their associated networks are likely to provide the molecular basis for understanding and intervening in visual, often blinding diseases. Again, electron microscopy, structural mass spectrometry techniques and X-ray crystallography are used not only to understand the visual system, but by extension the signalling networks of other GPCRs as well. In longstanding collaboration Krzysztof Palcewski (Pharmacology), Mark Chance (Proteomics) and David Lodowski (Proteomics) have utilized electron microscopy along with previously determined X-ray structures to build models of how dimers of rhodopsin interact with transducing to propagate the visual signal, also downstream with phosphodiesterase. The models are then interrogated and validated with a combination of confocal and two-photon microscopy and other biophysical and biochemical techniques along with gene expression and transgenic animal models. In the research of Philip Kiser (Pharmacology) employs X-ray crystallography, electron microscopy and spectroscopic methods to study the biochemistry, biophysics and physiology of a metabolic pathway known as the visual cycle that is essential for vision in vertebrates.

Human cancers

HUMAN CANCERS
Biology of cancer progression, proliferation and metastasis

The lab. of Matthias Buck (Physiology and Biophysics) studies two families of receptors (Plexins and Ephs) involved in the regulation of cell migration and cancer metastasis using structural biology, biophysical and simulation methods. Mark Chance (Proteomics) focuses on the structure and dynamics of GPCRs and ion channels using novel mass spectrometry approaches. The John Mieyal (Pharmacology) is focused on molecular mechanisms and physiological implications of thiol-disulfide oxidoreductase enzymes. The team of Jun Qin (Cleveland Clinic) focuses on the structural basis of integrin-mediated cell adhesion and migration using NMR techniques. Derek Taylor (Pharmacology) is interested in the assembly, structure, and function of telomere and telomerase. Eckhard Jankowsky's group (Biochemistry) uses fluorescence and other biophysical approaches to examine roles of RNA helicases.

With the aim to design/improve Cancer therapeutics, Chris Dealwis works on structure-function studies of the cancer target ribonucleotide reductase and develops novel chemotherapies. Jun Qin also develops structure-based small molecules that may inhibit dysfunctional integrin signaling during cancer progression. The group of Sichun Yang (Proteomics) is focused on the molecular biophysics of hormone estrogen receptor, a key molecular target for breast cancer therapeutics using novel theoretical and computational approaches.

Metabolic Disease

METABOLIC DISEASES

Several sbb-tp faculty are focused on elucidating molecular and cellular changes responsible for human metabolic diseases. Rajesh Ramachandran (Physiology) is working to elucidate the various molecular mechanisms of proteins that regulate intracellular membrane remodeling and trafficking events. Jason Mears's (Pharmacology) research team is pursuing a detailed understanding of the relationship between mitochondrial dynamics and human disease. The lab of Charles Hoppel (Pharmacology) is focused on characterizing bioenergetic changes in individuals displaying mitochondrial dysfunction through alterations in fatty acid oxidation and/or defects in the electron transport chain. Similarly at the enzymatic level, John Mieyal (Pharmacology) is utilizing a range of cellular, molecular, and structural biology approaches to delineate the molecular basis for glutaredoxin catalysis and its role in regulation of fundamental cellular processes. Vivian Yee (Biochemistry) and her lab are solving structures of biotin-dependent enzymes to determine their catalytic mechanisms as well as the structural consequences of human disease mutations. In the realm of signal transduction the research team of George Dubyak (Physiology & Biophysics) studies how nucleotide-based signals regulate vasodilation, hemostasis, and inflammation. Michael Weiss (Biochemistry) is a world-recognized diabetes researcher studying insulin signaling and working on the development of new insulin analogues that better maintain blood sugar levels. The lab of Walter Boron (Physiology & Biophysics) is a pioneer in acid-base homeostasis and how pH is regulated within cells. Tsan (Sam) Xiao's lab (via Physiology & Biophysics) studies the structure, function and regulation of inflammasomes in autoimmune/autoinflammatory disorders and infectious diseases.