CLP/ NIH GRADUATE TRAINING PROGRAM SEMINAR
Structure, mechanism and pharmacological inhibition of membrane proteins from influenza A virus M2 proton channel to integrins
Bill DeGrado, PhD, Professor of Pharmaceutical Chemistry, Department of Pharmaceutical Chemistry, University of California, San Francisco
Monday, September 17
4:00 pm | Pancoe Auditorium
Coffee and dessert will be served at 3:45 pm
William DeGrado’s research group focuses on structural characterization of membrane proteins and de novo protein design in order to understand biological processes relevant to human disease and develop novel therapeutics.
They approach many diverse biological issues:
Protein design: They use de novo protein design to test whether our knowledge has advanced sufficiently to allow generation of structure and function from first principles. Our lab also uses this method to incorporate desired features into biological systems.
Integrin inhibitors: They study the mechanisms of signal transduction and conformational change in integrins, and have also designed novel small molecule inhibitors of specific integrins to use as therapeutics for tissue fibrosis and other diseases.
Antimicrobials: We study the mechanism of action of and bacterial response to rationally designed small molecule mimics of antimicrobial peptides.
Influenza: Thy study the matrix 2 protein (M2) of influenza A, which is a drug target found in the viral envelope of the flu.
HIV: We aim to characterize the membrane proximal external region of HIV-1’s envelope protein to rationally design an HIV vaccine.
Alzheimer’s disease: They are interested in structurally characterizing and disrupting the accumulations of Aβ that are associated with Alzheimer’s disease.
Bacterial sensing: They are interested in the mechanisms by which bacteria sense their environment and adapt to different environmental stresses.
Computational tools: They have taken a nature-inspired approach to protein design.
The M2 proton channel from influenza A virus is an essential component of the viral envelope, and this protein is required for acidification of the inside of the virus once engulfed by the endosome. M2 is also the target of the anti-influenza drugs amantadine and rimantadine, although drug-resistance has become a major problem in the last decade. To investigate the mechanism by which protons are transported along water wires through the channel we have determined very high resolution crystal structures at room temperature and using X-ray free electron laser crystallography. The structures provide insight into the mechanism by which protons diffuse through clusters of water molecules to histidine residues deep within the pore. We next used this structural insight to design new drugs that inhibit the most problematic drug-resistant mutant forms of the channel.
Next I will discuss the design of inhibitors of the integrin avb1 that block local activation of TGF-b, and the use of these drugs for the treatment of fibrotic disorders. Finally, I will discuss a new role for integrin-mediated interactions between airway smooth muscle cells and the extracellular matrix in severe asthma, and the development of inhibitors that block this process.
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.
Hosted by CLP Trainee Elizabeth Johnson. This is a required activity for CLP Trainees. Supported by the Chemistry of Life Processes Predoctoral Training Program NIH/ NIGMS 5T32GM105538-06.