David W Rodgers, PhD

The focus of our work is understanding the basis for enzyme catalysis and developing the ability to manipulate macromolecules for the treatment of diseases and other practical applications. Our studies fall into several broad areas:



Protein engineering and the molecular mechanisms of substrate recognition and catalysis.



We are deciphering the molecular mechanisms underlying several biological processes using structural techniques, particularly x-ray crystallography, and functional analyses. One project is to understand the basis for the unusual substrate recognition shown by neuropeptidases, enzymes that inactivate or modify the activity of peptide neurotransmitters or neurohormones. These enzymes cleave only small peptide substrates, not proteins or larger peptides, and they specifically recognize a variety of seemingly unrelated cleavage sites. Our recent high-resolution crystal structure of the neuropeptidase neurolysin suggests possible molecular mechanisms for these unusual properties and efforts are underway to test these hypotheses. Ultimately, we hope to engineer peptidases that cleaoal is to understand substrate recognition and the basis for the oxidation-reduction properties of this enzyme so that we may reengineer its properties for specific tasks.



Development of novel therapeutics for psychotic disorders, drug addiction, and pain relief.



Small peptide neurotransmitters and neurohormones control or influence many aspects of human perception and behavior. In collaboration with a pharmaceutical company, we are attempting to design inhibitors of two enzymes that control the levels of a particular peptide associated with the development of psychotic disorders, pain perception, and addiction. We use high-resolution structural techniques and computational methods to improve the characteristics of compounds identified by high-throughput screening. Our goal is to produce highly specific and bioavailable inhibitors of the target enzymes that can be tested in clinical trials.



Molecular bases for severe immunodeficiency disorders and congenital myasthenic syndromes.



 We are using a combination of structural techniques, mutagenesis, and functional analysis to understand the basis for inherited mutations associated with disease in two different systems. As part of our efforts to understand the molecular mechanisms involved with V(D)J recombination, we are attempting to understand how mutations in the recombinases associated with this process affect their function. These recombinase mutations cause a number of life-threatening immunodeficiency disorders. We are also attempting to understand the effects of inherited mutations in choline acetyltransferase, the enzyme responsible for the synthesis of the neurotransmitter acetylcholine. These mutations have recently been shown to cause some types of congenital myasthenic syndrome, a frequently fatal motor disorder in infants.