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Structural and Chemical Biology of Membrane Proteins
- Anirban Banerjee, PhD, Head, Unit on Structural and Chemical Biology of Membrane Proteins
- Eric Christenson, PhD, Postdoctoral Fellow
- Pramod Kumar, PhD, Postdoctoral Fellow
- Chul-jin Lee, PhD, Postdoctoral Fellow
- Mitra Rana, PhD, Postdoctoral Fellow
- Raffaello Verardi, PhD, Postdoctoral Fellow
Cell membranes lie at the heart of cellular compartmentalization. Integral membrane proteins that are embedded in cell membranes perform critically important processes, exemplified by the propagation of electrical signals along the cellular surface, exchange of material between two cellular compartments, and response of a cell to numerous signaling cues. We are interested in the structural basis of the functions of several integral membrane protein families. Our approach calls for a combination of x-ray crystallography with functional analyses and a range of biochemical and biophysical techniques. In addition to solving high-resolution structures and using them to guide functional experiments, we also carry out experiments to investigate the role of membrane lipids in modulating the structure and function of membrane proteins. The experiments will provide novel insights into the structure and function of the membrane proteins and thus lead to new discoveries in the cellular processes in which they participate. Malfunctioning of the processes is the cause of a wide range of human disorders such as multiple sclerosis, ataxia, and various forms of neurodegenerative disease, to name but a few. Thus, in the process, we will also gain important insights into the biological underpinnings of these diseases.
Structural studies of toxin block of K+ channels
Potassium-selective channels (K+ channels) are a large, diverse group of integral membrane proteins, crucial for proper cellular functioning. Toxins from animal venoms are able to specifically inhibit ion conduction by specific K+ channel subtypes by binding to different parts of the channel; the toxins have thus emerged as indispensable tools in neuroscience. However, there is a dearth of available co-crystal structures of K+ channel–toxin complexes, and thus the structural bases for recognition of specific K+ channels by specific toxins remain obscure. Currently, we are pursuing the structures of K+ channels with toxins, specifically, dendrotoxin, isolated from snake venom. Given that different parts of K+ channels are targeted by different toxins, the structure of each distinct class of toxin–channel complexes will lead to insights into unique aspects of this very important class of ion channels and their role in cellular physiology.
Molecular mechanism of iron transport
We are focusing on mitochondrial inner membrane transporters that bring iron into mitochondria. Subsequently, the iron is used in the biosynthesis of heme, a central component of the heme in hemoglobin, myoglobin, and cytochromes, and in the biosynthesis of iron-sulfur clusters, important cofactors required for proteins involved in a wide range of cellular activities, viz. electron transport in respiratory chain complexes, regulatory sensing, photosynthesis, and DNA repair. We are currently using heterologous expression to obtain enough purified material for biochemical and biophysical characterization.
Structural and chemical biology approach to design novel antibiotics
Antibiotic-resistant pathogenic bacteria pose a major threat to our healthcare systems. In the face of this challenge, there is a pressing need to identify new targets for combating antibiotic-resistant bacteria and to identify and develop therapeutic leads that can result in clinically useful drugs. Clinically approved antibiotics that are currently in use mostly target bacterial cytosolic enzymes and the ribosome. Integral membrane proteins are, however, a largely uncharted territory for antibiotic development, owing to the difficulty in handling and purification, and importantly, to the lack of structural information. In collaboration with Clifton Barry’s lab, we propose to combine fragment-based drug discovery (FBDD) and high throughput screening (HTS), together with high-resolution structural analyses, to target integral membrane proteins involved in bacterial cell envelope biosynthesis and to develop leads for novel antibacterial therapies. In the process, we hope to make fundamental discoveries regarding the mechanistic underpinnings of bacterial cell envelope biosynthesis.
Additional Funding
- NIH Director's Challenge Award
Collaborators
- Clifton E. Barry, III, PhD, Laboratory of Clinical Infectious Diseases, NIAID, Bethesda, MD
Contact
For further information, contact anirban.banerjee@nih.gov.
