We are investigating the molecular basis for substrate recognition and inhibitor action in neuropeptidases. These enzymes play key roles in the generation and inactivation of peptide neurotransmitters and hormones. A better understanding of these enzymes and the development of specific inhibitors may permit novel therapies for psychotic disorders, pain, and drug and alcohol addiction. We study one enzyme, neurolysin, as a model system. Like a number of the neuropeptidases, it is active only on short peptides, and it is able to recognize a diverse but specific set of cleavage sites. This enzyme is known to control the levels of neurotensin, which is one of the most potent analgesics known and is thought to play a role in schizophrenia and depression. Our group has determined a crystal structure of neurolysin, which is a 78kDa zinc metallopeptidase. We now plan to determine crystal structures of the enzyme complexed with peptides and inhibitors to determine the basis for the unusual aspects of its substrate recognition. This structural work will be complemented by a series of functional studies aimed at better defining the features of a good substrate. And finally, we will compare the mechanisms of substrate recognition and inhibitor binding with those of a neuropeptidase from a different enzyme family

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30DA014596-01
Application #
6294351
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (01))
Program Officer
Babecki, Beth
Project Start
2001-05-01
Project End
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
1
Fiscal Year
2001
Total Cost
$38,862
Indirect Cost
Name
University of Kentucky
Department
Biochemistry
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Ray, Kallol; Hines, Christina S; Coll-Rodriguez, Jerry et al. (2004) Crystal structure of human thimet oligopeptidase provides insight into substrate recognition, regulation, and localization. J Biol Chem 279:20480-9