Jump to main content
US EPA
United States Environmental Protection Agency
Search
Search
Main menu
Environmental Topics
Laws & Regulations
About EPA
Health & Environmental Research Online (HERO)
Contact Us
Print
Feedback
Export to File
Search:
This record has one attached file:
Add More Files
Attach File(s):
Display Name for File*:
Save
Citation
Tags
HERO ID
1015682
Reference Type
Journal Article
Title
Solution structure of Mycobacterium tuberculosis NmtR in the Apo state: Insights into Ni(II)-mediated allostery
Author(s)
Lee, CW; Chakravorty, DK; Chang, F-MJ; Reyes-Caballero, H; Ye, Y; Merz, KM, Jr; Giedroc, DP
Year
2012
Is Peer Reviewed?
Yes
Journal
Biochemistry
ISSN:
0006-2960
EISSN:
1520-4995
Volume
51
Issue
12
Page Numbers
2619-2629
Language
English
PMID
22394357
DOI
10.1021/bi3001402
Web of Science Id
WOS:000301946300026
Abstract
Mycobacterium tuberculosis is an obligate human respiratory pathogen that encodes approximately 10 arsenic repressor (ArsR) family regulatory proteins that allow the organism to respond to a wide range of changes in its immediate microenvironment. How individual ArsR repressors have evolved to respond to selective stimuli is of intrinsic interest. The Ni(II)/Co(II)-specific repressor NmtR and related actinomycete nickel sensors harbor a conserved N-terminal α-NH(2)-Gly2-His3-Gly4 sequence. Here, we present the solution structure of homodimeric apo-NmtR and show that the core of the molecule adopts a typical winged-helix ArsR repressor (α1-α2-α3-αR-β1-β2-α5) "open conformation" that is similar to that of the related zinc sensor Staphylococcus aureus CzrA, but harboring long, flexible N-terminal (residues 2-16) and C-terminal (residues 109-120) extensions. Binding of Ni(II) to the regulatory sites induces strong paramagnetic broadening of the α5 helical region and the extreme N-terminal tail to residue 10. Ratiometric pulse chase amidination mass spectrometry reveals that the rate of amidination of the α-amino group of Gly2 is strongly attenuated in the Ni(II) complex relative to the apo state and noncognate Zn(II) complex. Ni(II) binding also induces dynamic disorder on the microsecond to millisecond time scale of key DNA interacting regions that likely contributes to the negative regulation of DNA binding by Ni(II). Molecular dynamics simulations and quantum chemical calculations reveal that NmtR readily accommodates a distal Ni(II) hexacoordination model involving the α-amine and His3 of the N-terminal region and α5 residues Asp91', His93', His104, and His107, which collectively define a new metal sensing site configuration in ArsR family regulators.
Tags
IRIS
•
Arsenic Hazard ID
1. Initial Lit Search
PubMed
WOS
WOS
Considered New
2. Lit Search Updates through Oct 2015
WOS
Considered
4. Considered through Oct 2015
6. Cluster Filter through Oct 2015
7. Other Studies through Oct 2015
Other
•
Arsenic (Inorganic)
1. Literature
PubMed
Web of Science
Lit search updates through Oct 2015
3. Hazard ID Screening
Other potentially supporting studies
4. Adverse Outcome Pathways/Networks Screening
Excluded/Not relevant
Title/Abstract screening
•
Arsenic MOA
1. MOA Literature Screening
MOA Cluster
3. Excluded
Other not relevant
Dragon Screened
Home
Learn about HERO
Using HERO
Search HERO
Projects in HERO
Risk Assessment
Transparency & Integrity