Our research focuses on small molecule and protein design as an approach to understanding macromolecule structure and function.
In the UC San Francisco lab of William DeGrado, PhD, we study the structural characterization of membrane proteins and de novo protein design in order to understand biological processes relevant to human disease and to develop novel therapeutics.
One primary research interest is de novo design, in which one designs proteins beginning from first principles. This approach critically tests our understanding of protein folding and function, while also laying the groundwork for the design of proteins and biomimetic polymers with properties not seen in nature.
De novo design of proteins has proven to be a useful approach for understanding the features in a protein sequence that cause it to fold into its unique three-dimensional structure. It has been possible to design functionally interesting proteins that bind redox-active cofactors, DNA, and transition metals. This approach has been extended to the design of membrane-active proteins, including ion channels, antibiotics, and fusogenic agents.
We also study the structures and functions of a number of pharmacologically interesting systems, including:
- Structure of the M2 proton channel from the influenza A virus
- Signal transduction of integrins
- Small molecule inhibitors of integrins
- Antimicrobial host-defense protein mimics, which show considerable promise for treating antibiotic-resistant infections
- Molecules that target protein structures critical to the pathogenesis of HIV and Alzheimer’s disease
The DeGrado Lab has consistently been at the forefront of using chemical, biophysical, and computational methods to tackle key problems in biological systems. For example, rapidly occurring mutations within HIV and influenza viruses are rendering existing treatments ineffective and could possibly lead to a pandemic. Similarly, the increasing prevalence of drug-resistant bacterial infections require the development of novel points of attack to have any recourse against these infections. With the aging of the baby boomer population, age-related neurodegenerative diseases like Alzheimer’s disease are becoming more prevalent, and fast action in understanding disease pathogenesis and developing effective therapeutics is desperately needed. The DeGrado Lab draws on expertise in a diverse set of basic science technologies to combat these current health crises.
Our lab leverages structural data to rationally design proteins and small molecules. The Protein Data Bank (PDB) provides a rich source of structural information on proteins and ligand binding sites. In the last few years, few new globular protein folds have been discovered, suggesting we have exhaustively sampled them. Thus, we can confidently mine these structures for common motifs to incorporate into our designed proteins and protein-ligand interactions, using computational tools. However, fewer membrane protein structures are available in the PDB. We are studying several transmembrane proteins and designing new ones in hopes of adding to this small but growing body of knowledge.
The Department of Pharmaceutical Chemistry at the UCSF School of Pharmacy has an excellent and stimulating environment. Our location in the Cardiovascular Research Institute (CVRI) is just a small part of the rich research environment of the Mission Bay campus, and we collaborate with the Institute for Neurodegenerative Diseases (IND), the California Institute for Quantitative Biosciences (QB3), the Helen Diller Family Comprehensive Cancer Center, and the Gladstone Institutes. UCSF is a world-renowned scientific hub, housing a number of state-of-the-art core facilities that are critical to our work. These include high-throughput DNA sequencing at the Human Genetics Core Facilities (GCF), the Mass Spectrometry Facility (MSF), and the Cancer Center Core Facilities which include equipment and staff to support genome analysis, cell analysis, informatics, mouse pathology, tissue histology, and microarray construction and analysis. We also interact closely with the Small Molecule Discovery Center (SMDC) to design and develop novel small molecules with therapeutic potential.
Postdocs, graduate students, staff scientists, and visiting scholars in the DeGrado Lab hail from many backgrounds, including synthetic organic chemistry, computer science, X-ray crystallography, NMR spectroscopy, bioengineering, and even astrophysics. This multidisciplinary group is uniquely poised to bring new insight to scientific questions in medicinal chemistry, biophysics, and structural biology at UCSF.