Structural Biology Program in Physiology

research photo Every cell, prokaryotic and eukaryotic alike, is subject to its environment. A cell needs to continuously respond to chemical, physical and biological extra-cellular stimuli. This is achieved by proteins that reside within the membrane, and that are responsible for how a cell exchanges information with the outside. For example, there are channels that regulate the flux of ions or nutrients across the membrane, and receptors that are activated by specific ligands to elicit an intra-cellular response.

A snapshot of any and every one of such molecules at the atomic level is of invaluable importance in understanding how the protein in question works in both physiological and pathological states of the cell.

Membrane proteins constitute 30% of all human proteins and ~60% of drug targets. Yet, they only represent less than 1% of protein structures determined to date. Obtaining a macromolecular structure typically entails measuring X-ray diffraction data from suitable protein crystals. Producing crystals sufficiently ordered to yield quality X-ray diffraction thus allowing structural investigation, is the key and most problematic step. This is especially difficult for membrane proteins because they naturally reside in the cellular membrane, and therefore have to be extracted by detergents for purification and crystallization. Detergents are a poor substitute of the lipid bilayer and often lead to protein destabilization and denaturation.

The Structural Biology Program within the Department of Physiology and Cellular Biophysics strives to determine high-resolution structures of the main protein components involved in cellular signaling events. The program brings together the expertise of Dr. Wayne A. Hendrickson, Dr. Filippo Mancia and Dr. Andrew Marks within the Department, of Dr. Lawrence Shapiro and Dr. Alexander Sobolevsky from the Department of Biochemistry and Molecular Biophysics, and of Dr. Qing Fan from the Department of Pharmacology.

We have assembled over the last 3 years a common core facility for automated set-up, storage, visualization and optimization of crystallization experiments which is unique and absolutely state of the art. Furthermore, Drs. Hendrickson, Mancia, Shapiro and Sobolevsky are all part of the New York Consortium of Membrane Protein Structure. This is an NIH-funded initiative in which at a central facility located in the close-by New York Structural Biology Center, high-throughput methodologies are used to select membrane proteins with increased probability of crystallization. These are then distributed to the individual labs for scale-up, crystallization and structure determination efforts. The probability of obtaining crystals from anyone of these preselected targets is in the 5-10% range, up from the 0.1% typically observed for crystallization of membrane proteins.

Qualified graduate students and postdoctoral scientists are encouraged to apply for positions

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