The Wilson Laboratory TSRI

Crystallographic Studies of Immune Recognition, Viral Pathogens, and Anticancer Targets.

Immunologic recognition of microbial pathogens is fundamental for fighting infectious disease. One of our major goals is to understand the interaction of foreign antigens with the immune system through high-resolution x-ray structural studies of antibodies and antigens in the humoral system, T-cell receptor complexes with MHC class I and class II in the cellular system, and through pattern recognition receptors in the innate immune system. Many crystal structures of monoclonal Fab fragments and complexes with a variety of antigens, such as peptides, steroids, cocaine, and proteins, including HIV-1, gp120 and gp41, have led to significant insights into antibody-antigen recognition, virus neutralization, and vaccine design for HIV-1. In addition, catalytic antibodies, many of which carry out disfavored reactions or for which no natural enzymes exist have given us insight into the use of these artificial catalysts. The T-cell receptor in complex with pMHC has revealed how peptide antigens can be recognized in the context of the MHC molecule. Many other key molecules in cellular immunology are being studied, such as non-classical or MHC homologues: for example, CD1 binds lipid, glycolipid, and lipopeptide antigens from the cell walls of microbial pathogens and the NK family of receptors can recognize classical as well as distant MHC homologues. Recent studies on other pattern recognition receptors, include peptidoglycan recognition protein (PGRP), TREM-1, and Toll-like receptors (TLR) are now revealing how unique pathogen associated molecules can be recognized by the immune system. Also, the 1918 flu, which killed 20-40 million people worldwide, is being reinvestigated through structural studies of the 1918 viral proteins, such as the hemagglutinin and neuraminidase. Another major project is concerned with inhibitors of glycinamide ribonucleotide transformylase and ATIC enzymes that catalyze the enzymatic steps that require reduced folate cofactors in the purine biosynthetic pathway. These enzymes represent novel targets for antineoplastic intervention.