Structure Determination of Mycobacterium tuberculosis Serine Protease Hip1 (Rv2224c)

Naffin-Olivos, Jacqueline L.; Daab, Andrew; White, Andre; Goldfarb, Nathan E.; Milne, Amy C.; Liu, Dali; Baikovitz, Jacqueline; Dunn, Ben M.; Rengarajan, Jyothi; Petsko, Gregory A.; Ringe, Dagmar

doi:10.1021/acs.biochem.6b01066

Structure Determination of Mycobacterium tuberculosis Serine Protease Hip1 (Rv2224c)

Journal Article · Fri Apr 07 00:00:00 EDT 2017 · Biochemistry

DOI:https://doi.org/10.1021/acs.biochem.6b01066· OSTI ID:1368260

^[1]; Daab, Andrew ^[1]; White, Andre ^[1]; Goldfarb, Nathan E. ^[2]; Milne, Amy C. ^[1]; Liu, Dali ^[3]; Baikovitz, Jacqueline ^[1]; Dunn, Ben M. ^[4]; Rengarajan, Jyothi ^[5]; Petsko, Gregory A. ^[6]; Ringe, Dagmar ^[1]

Brandeis Univ., Waltham, MA (United States)
California Health Sciences Univ., Clovis, CA (United States)
Loyola Univ. Chicago, Chicago, IL (United States)
Univ. of Florida, Gainesville, FL (United States)
Emory Univ., Atlanta, GA (United States)
Cornell Univ., Ithaca, NY (United States). Weill Medical College

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Institutes of Health (NIH)

OSTI ID:: 1368260

Alternate ID(s):: OSTI ID: 1409616

Journal Information:: Biochemistry, Journal Name: Biochemistry Journal Issue: 17 Vol. 56; ISSN 0006-2960

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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