Structural Biology Faculty

The research of the primary and secondary faculty that use structural biology techniques are listed below along with a short description of their work.

Karen Anderson Structural and functional studies on proteins that are molecular targets for antiviral, antimicrobial, antiparasitic therapies. Our lab is interested in mechanistic and structural studies of HIV-1 reverse transcriptase, an important target for the design of novel therapies to treat AIDS. We are also studying a class of bifunctional proteins having two different catalytic activities that are unique to parasitic protozoa. These protozoal pathogens are responsible for life-threatening opportunistic infections in AIDS patients as well as malaria which is a serious world health problem.

Titus Boggon Rearrangementof the actin cytoskeleton is a critical for cellular structure, cell division,motility, intracellular transport, and a variety ofother functions. Rho smallGTPase signaling cascades are key regulators of these rearrangements, and our goal is to answer the question:“What are the molecular mechanisms that control Rho signaling cascades?”To do this we use X-ray crystallography, cryo-electron microscopy, small-angle X-ray scattering, biochemistry, biophysics and cellular studies. Illustrative topics that we have addressed include: discovering how a Rho effector kinase is autoregulated, defining a unique kinase-substrate interaction that controls actin depolymerization, and discovering new pseudoGTPase domains in an important RhoGAP protein. We also probe the regulation mechanisms ofa Rho-associated signaling pathway which causes a severe neurovascular disorder. Overall, our lab hopes to significantly improve the molecular level understanding of these important pathways.

David Calderwood Signaling through integrin adhesion receptors. Dynamic, and tightly regulated, adhesion of cells to the extracellular matrix that surrounds them is essential for development, wound healing, the immune response, hemostasis and cell migration. Disruption of normal adhesion and adhesion signaling contributes to inflammatory, auto-immune and cardiovascular diseases and tumor metastasis, making these promising pathways for therapeutic intervention. We combine the tools of structural biology, biochemistry and cell biology to investigate how intracellular signals regulate integrin cell adhesion receptors and how integrin-mediated signaling and linkage to the cytoskeleton control cell adhesion, migration, morphology, and mechanosensing.

Barbara Ehrlich Structure-function of intracellular calcium channels. We study how structural features can be used to predict the function of the channels that release calcium from intracellular stores, In particular, we are interested in how calcium binding can regulate the shape and activity of the intracellular channels, polycystin 2 and the InsP3R, and how structure and function are altered in disease

Kathryn Ferguson We use cryo-electron microscopy, X-ray crystallography and a wide range of biophysical techniques to understand the relationship between receptor structure and activity, with a particular focus on receptor tyrosine kinases (RTKs). We study both soluble fragments and intact RTKs. We are particularly interested in how the native membrane environment influences receptor structure and function, which will inform new strategies to modulate RTKs pharmacologically.

Ya Ha Intramembrane proteases. We use x-ray crystallography to solve structures of these membrane proteins with the hope that the structural knowledge will shed light on their mechanism of action, explain mutations that cause human disease, and help drug development.

Daryl Klein Our primary research interest is to decipher the control logic that regulates signaling relays important for the development of cancer and metastasis. Such regulatory principles are often hard-wired into the physical, thermodynamic and kinetic parameters of each system. We therefore approach our studies “bottom up” –building from an atomistic perspective. Our goal is to reveal, and ultimately harness the signaling logic to rewrite oncogenic programs in cancer. Our studies primarily target proteins found onthe surface of cancer cells. These include adhesion molecules, receptor kinases/phosphatases and immune checkpoint sensors.

Mark Lemmon A major focus of the Lemmon lab has been to understand transmembrane signaling by growth factor receptor tyrosine kinases (RTKs), of which there are 58 in the human proteome that fall into 20 different families. Mutations in almost all of these RTKs –someactivating, some inactivating –cause cancer or other diseases, making the RTKs important therapeutic targets. We are interested in understanding how these receptors signal, and –importantly –how RTK mutations seen in afflicted patients affect receptor activity. We combine cellular, biochemical, and structural approaches to understand molecular mechanisms of RTK signaling, doing our best to exploit this mechanistic understanding to advance development and application of receptor-targeted therapeutics. Collaborating closely with geneticists and clinical investigators, our goal is to link detailed mechanistic understanding to biology in the intact organism (or patient). In recent work, we discovered how alterations in the lifetime of the activated EGF receptor might underlie biased agonism by its different ligands. Another key focus is to determine how RTKs with intracellular pseudokinases function -particularly in Wnt signaling. Although much of our work has focused on RTKs and RTK signaling, we are also very interested in other poorly understood receptors –one recent new direction being mechanistic aspects of immunomodulatory co-receptors such as Tim3.

Elias Lolis Inflammatory proteins. Our focus is in (1) chemokines and their interactions with glycosaminoglycans and G-protein coupled receptors, and (2) macrophage migration inhibitory factor (MIF) and its interaction with small molecules and its receptors. Besides inflammation, these proteins are involved in cancer, HIV-1 infection, autoimmune disorders, and genetic diseases (e.g., WHIM syndrome). Our goal is to use structural biology (X-ray crystallography and NMR) to develop a better understanding of the mechanism of action of these proteins for the developing of therapeutics.

Gary Rudnick Mechanism of membrane transport.The availability of X-ray crystal high resolution structures of membrane transport proteins has opened a window of insight into their function. We are particularly interested in neurotransmitter transporters and the conformational changes that accompany transmitter translocation and inhibitor binding. The effects of ligand binding on conformation mediate ion-neurotransmitter coupling and are responsible for the ability of neurons to accumulate transmitters.These transporters are targets for antidepressant drugs and psychostimulants such as amphetamines and cocaine. A combination of structural, biochemical and computational analysis has provided new insight into the mechanism of transport.

Joseph Schlessinger Our laboratory is using x-ray crystallography, Cryo electron microscopy (cryo-EM) and other biochemical and biophysical approaches to explore the mechanism of action of receptor tyrosine kinases (RTK),cytoplasmic protein kinases and proteins involved in mediating their intercellular signaling pathways. Our goal is to obtain a detailed molecular view of how RTKs are activated and how their cellular selectivity is controlled normally, in cancer and in other diseases.

Ben Turk We are interested in understanding how protein kinases target specific protein substrates, thus ensuring proper transmission of intracellular signals. Solving this problem requires elucidating the structural basis of kinase-substrate interactions, which we accomplish using a combination of structural biology, combinatorial library screening, and biochemistry. These approaches enable us to probe the consequences of disrupting these interactions as a means to unravel the molecular mechanisms of signal transduction in living cells.