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Rational design of tertiary coordination sphere of a heme-based sensor for two-orders enhanced oxygen affinity
Anoop Rama Damodaran1, Eaindra Yee1, Rahul L Khade2
1Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
Biorxiv : the Preprint Server for Biology
|June 12, 2025
Summary
Researchers enhanced oxygen (O2) sensing in a bacterial protein by modifying its heme iron
Area of Science:
- Biochemistry
- Molecular Biology
- Biophysics
Background:
- Biological oxygen (O2) sensing is vital for physiological functions.
- Heme proteins sense O2 by binding it to their iron center, with varying affinities.
- Mechanisms tuning O2 affinity in heme sensors are not fully understood.
Purpose of the Study:
- Investigate the role of the heme iron's tertiary coordination sphere in O2 affinity.
- Utilize the mycobacterial DosS protein as a model system for O2 sensing.
- Elucidate how modifications to the heme pocket influence O2 binding.
Main Methods:
- Rational and systematic modification of the DosS tertiary coordination sphere.
- Engineering a Trp-Tyr-Asn H-bond triad in the heme's distal pocket.
- Structural, biochemical, spectroscopic, and computational analyses of wild-type (WT) and designed DosS variants.
Main Results:
- Enhanced O2 affinity in designed DosS variants by over 150-fold.
- Achieved a Kd value of 3 ± 1 nM for designed DosS, compared to 460 ± 80 nM for WT DosS.
- Demonstrated the interplay between distal H-bond networks and heme-pocket electrostatics in O2 sensing.
Conclusions:
- The tertiary coordination sphere significantly modulates O2 affinity in heme-based sensors.
- H-bond networks and electrostatics within the heme pocket are key determinants of O2 sensing capabilities.
- Metalloenzymes can dramatically alter sensitivity to diatomic signaling molecules through tertiary coordination sphere tuning.
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