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Nair, D., & Crane, B. R. (2026). Structure and dynamics of a multidomain nitric oxide synthase regulated by a c2 domain. Science Advances, 12(8), eaeb4529. 
Added by: Dr. Enrique Feoli (02/03/2026, 16:39)   Last edited by: Dr. Enrique Feoli (02/03/2026, 17:36)
Resource type: Journal Article
DOI: 10.1126/sciadv.aeb4529
BibTeX citation key: Nair2026
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 Categories: BioAcyl Corp
Subcategories: Entero-salivary cycle
Creators: Crane, Nair
Collection: Science Advances		 Views: 7/16
Abstract
Nitric oxide synthase (NOS) is a widely studied multidomain redox enzyme that produces the key signaling molecule and cytotoxic agent nitric oxide (NO) for functions that range from mammalian vasodilation to prokaryotic antibiotic resistance. NOS enzymes from metazoans and cyanobacteria rely on dynamic associations of their oxygenase and coupled diflavin reductase domains that have largely evaded detailed structural characterization. Cryo–electron microscopy studies of a representative dimeric six-domain Synechococcus NOS reveal the architecture of the full-length enzyme, which contains an unusual regulatory C2 domain, and additional nitric oxide dioxygenase (NOD) and pseudoglobin modules. Five distinct structural states depict how pterin binding couples to tight and loose oxygenase conformations and how the Ca2+-sensitive C2 domain moves over 85 angstroms to alternatively regulate either the NOS or NOD heme center. The extended carboxyl-terminal tail and its dynamic interactions highlight an added layer of regulation required by multidomain NOSs compared to other diflavin reductases. syNOS is a highly dynamic multidomain oxidoreductase that harnesses a Ca2+-sensitive C2 domain to modulate activity.
Added by: Dr. Enrique Feoli  Last edited by: Dr. Enrique Feoli
Notes

Model for NOS to NOD activity switching in syNOS.
In the inactivated locked state, syNOSOxy equilibrates between a loose and tight dimer, the latter stabilized by BH4. This state can transition into the asymmetric NOD active state, which involves a release of a C2 domain from one subunit and increased mobility of NOSFld and NOSFNR, such that NOSFNR can reduce the syNOSGlb to activate NOD activity. syNOSGlb reduction coincides with a loosening of the CTT to allow hydride transfer from NADPH to FAD and movement of syNOSFNR. In the presence of Ca2+/NADPH/l-Arg, syNOS rearranges to facilitate NOS activity. The displacement of syNOSC2 from NOSOxy and its binding to NOSGlb relieve constraints on L2 and exposes the Trp715 site such that NOSFNR can relocate to NOSOxy on the opposing subunit and reduce the NOSOxy heme for NO production. 
 

 

Diagram of syNOS enzyme transitions with embedded kinetic parameters. Show three states: Locked (symmetrical dimer), Asymmetric NOD (C2 detached from one subunit, Fld/FNR mobile, Glb reduced), NOS Active (Ca²⁺, NADPH, L-Arginine trigger full NO synthesis). Use oversized pastel-colored labels. Annotate Asymmetric NOD state with turnover NOD ≈ 5 s⁻¹ and NOS Active state with turnover NOS active (k_cat ≈ 20 s⁻¹). Include directional arrows for domain transitions and electron flow. Legend box should explain: C2 (blue) = calcium-dependent regulatory module; Oxy (yellow) = catalytic core for NO synthesis; Fld (green) = electron shuttle; FNR (red) = reductase transferring electrons from NADPH; Glb (brown) = pseudoglobin module enabling NOD activity.

 

  • Asymmetric NOD State

    • Turnover NOD ≈ 5 s⁻¹

    • Reflects NO detoxification rate via Glb module

    • Fld and FNR domains are mobile, enabling electron transfer to Glb

  • NOS Active State

    • Turnover NOS active (kₐₜ) ≈ 20 s⁻¹

    • Full alignment of domains for NO synthesis

    • Electron flow: NADPH → FNR → Fld → Oxy → NO production


Added by: Dr. Enrique Feoli  Last edited by: Dr. Enrique Feoli
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