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Assistant Professor Linda S Brinen
The Sandler Center for Basic Research in Parasitic Diseases, Department of Cellular & Molecular Pharmacology
University of California, San Francisco
513 Parnassus Ave, HSW 517 Box 0511, San Francisco CA 94143-0511
Email: brinen@cmp.ucsf.edu
Tel: +1-415-514-3426
Fax: +1-415-502-8193
Homepage: http:// http://cmp.ucsf.edu/Faculty/pdb_show.html?id=brinen

Research
Our interests focus on the role of cysteine and serine proteases in two areas of biomedical concern: parasitic disease and allergy-induced asthma. In particular, we seek to obtain detailed atomic-level understanding of the structural determinants that affect selective and potent inhibition of the activity of cysteine protease involved in parasitic infection and allergic response.
The causative agents of Chagas’ disease, African sleeping sickness, malaria. fasciolosis and leishmaniasis (Trypanosoma cruzi, Trypanosoma brucei, Plasmodium falciparum, Fasciola hepatica, and several Leishmania species, respectively) each contain cysteine proteases that are critical to the life cycles of the organisms. Allergic asthma, a worldwide problem, is strongly correlated with immune sensitization to house dust mites. The mechanism by which antigens provoke intense allergic immune responses is unclear, however 75-80% of allergic asthmatics display mite sensitivity. Ten allergen groups have been isolated from house dust mites, including four proteases. As structure yields key insights into function and potential regulation, we use high-resolution X-ray crystallography to study proteases in their apo- or inhibitor (small molecule or endogenous macromolecular) -bound states. This allows for the mapping of chemical, electrostatic and steric topology involved in and near the enzyme’s active site. As structural information has been the basis for numerous advances in the development of new therapeutics in the last 25 years, insights obtained from both small and macromolecular complex structures are used in iterative cycles of rational design of inhibitors.
Collaborations
Professor James H. McKerrow (UCSF)
Professor Sharon L. Reed (UCSD)
Professor Jon Ellman (UCB)
Professor William Roush (Scripps Florida)
Professor Phillip Rosenthal (UCSF/SFGH)
Professor Magnus Abrahamson (Lund University)
Publications
Brinen LS, Hansell E, Cheng J, Roush WR, McKerrow JH, Fletterick RJ. A target within the target: probing cruzain’s P1’ site to define structural determinants for the Chagas’ disease protease. Structure 2000; 8: 831-840.
PMID: 10997902

Que X, Brinen LS, Perkins P, Herdman S, Hirata K, Torian BE, Rubin H, McKerrow JH, Reed SL. Cysteine Proteinases from distinct cellular compartments are recruited to phagocytic vesicles by Entamoeba histolytica. Mol. Biochem. Parisitol 2002: 119:23-32. PMID: 11755183

Que X, Ngo H, Lawton J, Gray M, Liu Q, Engle J, Brinen LS, Ghosh P, Joiner KA, Reed SL. The Cathepsin B of Toxoplasma gondii, toxopain-1 is critical for parasite invasion and rhoptry protein processing. J. Biol. Chem 2002; 277: 25791-25797. PMID: 12000756

Huang L, Brinen LS, Ellman JA. Crystal structures of reversible ketone-Based inhibitors of the cysteine protease cruzain. Bioorg Med Chem. 2003; 11(1):21-9. PMID: 12467703

Stack, CM, Donnelly S, Lowther J, Xu W, Collins PR, Brinen LS, Dalton JP. The Major Secreted Cathespin L1 Protease of the Liver Fluke, Fasciola hepatica: A LEU-12 TO PRO-12 REPLACEMENT IN THE NONCONSERVED C-TERMINAL REGION OF THE PROSEGMENT REMOVAL. J. Biol Chem. 2007 1;282(22):16532-43. PMID: 17403677

Stack, CM, Caffrey, C, Donnely, SM, Seshaadri, A., Lowther, J, Tort, JF, Collins, PR, Robinson, MW, McKerrow, JH, Craik, CS, Geiger, S, Marion, R., Brinen, LS, Dalton, J. Structural and functional relationships in the virulence-associated cathepsin L protease of the parasitic liver fluke, Fasciola hepatica. J. Biol Chem. 2008, Apr 11; 283 (15): 9896-908. PMID: 18160404.

Huang R, Que X, Hirata K, Brinen LS, Lee JH, Hansell E, Engel J, Sajid M, Reed S. The cathepsin L of Toxoplasma gondii (TgCPL) and its endogenous macromolecular inhibitor, toxostatin. Mol Biochem Parasitol. 2009 Mar;164(1):86-94. Epub 2008 Dec 6. PMID: 19111576 [PubMed - in process]

Kerr ID, Lee JH, Pandey KC, Harrison A, Sajid M, Rosenthal PJ, Brinen LS. Structures of falcipain-2 and falcipain-3 bound to small molecule inhibitors: implications for substrate specificity. J Med Chem. 2009 Feb 12;52(3):852-7. PMID: 19128015





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