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Title: Structure Determination of Mycobacterium tuberculosis Serine Protease Hip1 (Rv2224c)

Abstract

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

Authors:
ORCiD logo; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1409616
Report Number(s):
BNL-114668-2017-JA¿¿¿
Journal ID: ISSN 0006-2960
DOE Contract Number:
SC0012704
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemistry; Journal Volume: 56; Journal Issue: 17
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES

Citation Formats

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., and Ringe, Dagmar. Structure Determination of Mycobacterium tuberculosis Serine Protease Hip1 (Rv2224c). United States: N. p., 2017. Web. doi:10.1021/acs.biochem.6b01066.
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. Structure Determination of Mycobacterium tuberculosis Serine Protease Hip1 (Rv2224c). United States. doi:10.1021/acs.biochem.6b01066.
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., and Ringe, Dagmar. Fri . "Structure Determination of Mycobacterium tuberculosis Serine Protease Hip1 (Rv2224c)". United States. doi:10.1021/acs.biochem.6b01066.
@article{osti_1409616,
title = {Structure Determination of Mycobacterium tuberculosis Serine Protease Hip1 (Rv2224c)},
author = {Naffin-Olivos, Jacqueline L. and Daab, Andrew and White, Andre and Goldfarb, Nathan E. and Milne, Amy C. and Liu, Dali and Baikovitz, Jacqueline and Dunn, Ben M. and Rengarajan, Jyothi and Petsko, Gregory A. and Ringe, Dagmar},
abstractNote = {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},
doi = {10.1021/acs.biochem.6b01066},
journal = {Biochemistry},
number = 17,
volume = 56,
place = {United States},
year = {Fri Apr 07 00:00:00 EDT 2017},
month = {Fri Apr 07 00:00:00 EDT 2017}
}