Drennan Research and Education Laboratory: The Crystallographic Approach

The Drennan laboratory uses uses x-ray crystallography as a chief technique to study the structure and mechanism of metalloproteins. We focus on enzymes that contain complex metallocofactors and catalyze challenging chemical reactions, such as those that use radical-based chemistry or form organometallic bonds. We are interested in providing detailed three-dimensional information about the nature of complex metallocofactors to help understand how protein environment modulates reactivity. Using X-ray crystallography, we hope to gain insight into the function and mechanism of nature's complex protein machines.

Over the last few decades, advances in molecular biology, protein expression and purification, bioinformatics, computing power, and software development has made possible the structural determination of not just one enzyme, but several enzymes along an entire pathway. This has allowed us to better understand the interplay between enzymes in the production and manipulation of important metabolic molecules and natural products. Equally as important, these advances have also enabled us to solve mutiple structures of a single enzyme with bound substrates, analogs, and products, to acquire a series of "snapshots" of a single enzyme turnover. With these capabilities, X-ray crystallography has become a crucial element in studying enzyme mechanism.

Metalloproteins and Metalloenzymes -- The primary targets of research in the Drennan lab are enzymes that contain metals or metallocofactors. These metalloenzymes use the enhanced reactivity of transition metals to catalyze challenging chemical reactions including radical-based chemistry and manipulation of organometallic bonds. The lab is also interested in metalloproteins that sense changes in the cellular environment or act as redox mediators.

A structural approach to studying enzymes -- The Drennan lab combines X-ray crystallography with techniques from biochemistry and biophysics to understand enzyme mechanisms. We call like to call this approach “structural enzymology. At the atomic scale, we are interested in providing detailed three-dimensional information about the nature of complex metallocofactors to help understand how protein environment modulates reactivity. At the protein scale, we are interested in seeing how enzymes are constructed to control substrate access and specificity, and how they prevent loss of reactive intermediates or damage to expensive cofactors. At the largest scale, that of protein complexes, we want to know how proteins interact and how those interactions explain the observed behavior. Protein complexes are often large, have multiple distinct states, and can have large inter- and intrasubunit motions; therefore a single “snapshot” usually does not tell the entire story.