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Assay Development for High-Throughput Drug Screening Against Mycobacteria
Published on: October 25, 2024
DevS oxy complex stability identifies this heme protein as a gas sensor in Mycobacterium tuberculosis dormancy
Alexandra Ioanoviciu1, Yergalem T Meharenna, Thomas L Poulos
1Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, California 94158-2517, USA.
Biochemistry
|May 26, 2009
Summary
DevS kinase regulates Mycobacterium tuberculosis dormancy. Its ferrous-oxy complex stability, enhanced by interdomain interactions, indicates DevS functions as a gas sensor, not a redox sensor.
Area of Science:
- Microbiology
- Biochemistry
- Structural Biology
Background:
- DevS is a key sensor kinase regulating DevR activation and Mycobacterium tuberculosis entry into dormancy.
- Understanding DevS function is crucial for developing novel anti-tuberculosis strategies.
Purpose of the Study:
- To investigate the autoxidation rates and stability of the DevS ferrous-oxy complex.
- To elucidate the role of the Tyr171 residue in DevS oxygen sensing mechanism.
- To determine whether DevS functions as a gas or redox sensor in vivo.
Main Methods:
- Characterization of full-length wild-type DevS and its Y171F mutant.
- Assessing autoxidation rates in the presence of various cations and copper ions.
- Evaluating oxygen dissociation rates and kinase activity regulation.
Main Results:
- DevS forms a stable ferrous-oxy complex with low autoxidation rates in the presence of common cations.
- Copper ions (Cu2+) significantly accelerate DevS autoxidation.
- The Y171F mutation, disrupting a key hydrogen bond, did not alter protein stability or oxygen dissociation rates.
- Both wild-type and Y171F mutant DevS kinase activity are regulated by oxygen binding, with the ferrous five-coordinate complex being active and the oxy-ferrous six-coordinate species inactive.
Conclusions:
- DevS functions as a gas sensor in vivo, rather than a redox sensor.
- Interdomain interactions enhance the stability of the DevS ferrous-oxy complex.
- The findings provide insights into the molecular mechanism of DevS-mediated dormancy entry in M. tuberculosis.
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