Structure Determination of Mycobacterium tuberculosis Serine Protease Hip1 (Rv2224c)
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Naffin-Olivos J.L.
[8]
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- Daab A. [9] [6] ,
- White A. [8] ,
- et al
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Description
The Mycobacterium tuberculosis (Mtb) serine protease Hip1 (hydrolase important for pathogenesis; Rv2224c) promotes tuberculosis (TB) pathogenesis by impairing host immune responses through proteolysis of a protein substrate, Mtb GroEL2. The cell surface localization of Hip1 and its immunomodulatory functions make Hip1 a good drug target for new adjunctive immune therapies for TB. Here, we report the crystal structure of Hip1 to a resolution of 2.6 Å and the kinetic studies of the enzyme against model substrates and the protein GroEL2. The structure shows a two-domain protein, one of which contains the catalytic residues that are the signature of a serine protease. Surprisingly, a threonine is located within the active site close enough to hydrogen bond with the catalytic residues Asp463 and His490. Mutation of this residue, Thr466, to alanine established its importance for function. Our studies provide insights into the structure of a member of a novel family of proteases. Knowledge of the Hip1 structure will aid in designing inhibitors that could block Hip1 activity.
Subjects
Affiliations
- Appel Alzheimer's Disease Research Institute, Weill Cornell Medical College , New York, New York 10021, United States.
- Department of Biochemistry and Molecular Biology, University of Florida , Gainesville, Florida 32610, United States.
- Department of Biology, Brandeis University , Waltham, Massachusetts 02454, United States.
- Department of Chemistry and Biochemistry, Loyola University Chicago , Chicago, Illinois 60660, United States.
- Department of Pharmaceutical and Biomedical Sciences, California Health Sciences University , Clovis, California 93612, United States.
- Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02454, United States
- Division of Infectious Diseases, Department of Medicine, Emory Vaccine Center, Emory University School of Medicine , Atlanta, Georgia 30329, United States.
- Rosenstiel Basic Medical Sciences Research Center, Brandeis University , Waltham, Massachusetts 02454, United States.
- Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Massachusetts 02454, United States