Research Interests
The overall goal of the research in our laboratory is to relate the three-dimensional structure and dynamics of proteins to their biological functions. We use techniques of X-ray crystallography and other biophysical methods to elucidate the molecular structures, dynamics, and functions of proteins. Extensive use is made of modern computational methods to analyze the structures and their dynamics.
Biology with X-ray Free Electron Lasers (BioXFEL)
X-ray Free Electron Lasers (XFEL) produce a stream of unimaginably intense X-rays and in unimaginably short pulses, so intense and so rapid that they can capture the fastest biological processes. X-ray Free Electron Lasers offer a unique and exciting opportunity to explore biological mechanisms in areas that were previously thought impossible. To make full use of this multiple disciplines are required. Technology has to be developed for sample preparation and delivery; algorithms have to be developed to efficiently deal with massive quantities of data and to extract structural information. An educated community has to be developed to understand this information and the research possibilities that are incited. Today scientists can create amazingly detailed, three-dimensional images of molecules, through a process called X-ray crystallography. Such imagery provides a basis for
the rational design of drugs, and for an atomic understanding of life processes. For example, all of our  current anti-HIV drugs were developed using such images, but the process may fail. Molecular structures are derived from the patterns created when an X-ray beam bounces off a crystal, and breaks up into a family of secondary beams that flash out in all directions. BioXFEL will be developing the technology and infrastructure to support an astonishing new X-ray beam created at Stanford--a beam expanding new horizons to crystallography. Read More
Enzyme Discovery for Natural Product Biosynthesis (NatPro)
The goals of NatPro are to apply technologies developed by the Protein Structure Initiative (PSI) to problems of interest to the community of biologists and biochemists who investigate the role of natural products in human health and disease. The NatPro will play strong joint roles in both the identification of new natural product pathways and the subsequent discovery of new natural product-based pharmaceuticals by revealing the structures and active sites of novel enzymes, characterizing the enzymatic reactions of the gene products, identifying new natural products, and thus offering opportunities to identify and customize the pathways by altering specificities and/or identifying novel proteins or domains with desired enzymatic properties.
Natural products and their derivatives continue to play an important role in the drug pipeline. Over time, 7000 known structures have led to more than 20 commercial drugs, and about half of the new drugs approved in the last decade are based on natural products. Screening of new natural products and their analogs will continue, and be enhanced by modern methods such as metabolic engineering, synthetic biology, and structural analysis of compounds and the enzymes that produce them. For example, new biosynthetic routes are being built around engineered systems such as the modular polyketide synthases to produce new compounds. There are also still a tremendous number of new microbial natural products to be explored, as evidenced by the genomic sequencing data coming forth. Nevertheless, the discovery of new compounds remains an adventitious endeavor. Genome mining efforts to identify interesting clusters and to predict what natural products might come from these clusters of genes are beginning to produce hypotheses, however, the homology of the enzymes to known enzymes is generally low.   Read More