ArticleThe Journal of biological chemistry2014
Architecture of the nitric-oxide synthase holoenzyme reveals large conformational changes and a calmodulin-driven release of the FMN domain.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 48 citations in OpenAlex.
- Structure and dynamics of a multidomain nitric oxide synthase regulated by a C2 domain.Science advances · 2026Article
- Nitric Oxide Signaling in Cardiovascular Physiology and Pathology: Mechanisms, Dysregulation, and Therapeutic Frontiers.International journal of molecular sciences · 2026Review
- Detection of a clamp-shaped conformation of a neuronal nitric oxide synthase construct by pulsed EPR.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2025Article
- Analyzing the FMN-heme interdomain docking interactions in neuronal and inducible NOS isoforms by pulsed EPR experiments and conformational distribution modeling.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2024Article
- Mapping the Intersubunit Interdomain FMN-Heme Interactions in Neuronal Nitric Oxide Synthase by Targeted Quantitative Cross-Linking Mass Spectrometry.Biochemistry · 2024Article
- Probing calmodulin-NO synthase interactions via site-specific infrared spectroscopy: an introductory investigation.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2024Article
- Probing Protein Dynamics in Neuronal Nitric Oxide Synthase by Quantitative Cross-Linking Mass Spectrometry.Biochemistry · 2023Article
- Neutron scattering maps the higher-order assembly of NADPH-dependent assimilatory sulfite reductase.Biophysical journal · 2022Article
- Conformational states and fluctuations in endothelial nitric oxide synthase under calmodulin regulation.Biophysical journal · 2021Article
- Heat shock protein 90 enhances the electron transfer between the FMN and heme cofactors in neuronal nitric oxide synthase.FEBS letters · 2020Article
- Nitric oxide in cellular adaptation and disease.Redox biology · 2020Review
- Positional Distributions of the Tethered Modules in Nitric Oxide Synthase: Monte Carlo Calculations and Pulsed EPR Measurements.The journal of physical chemistry. A · 2019Article
- Effect of Macromolecular Crowding on the FMN-Heme Intraprotein Electron Transfer in Inducible NO Synthase.Biochemistry · 2019Article
- Tripping the light fantastic in membrane redox biology: linking dynamic structures to function in ER electron transfer chains.The FEBS journal · 2019Review
- Use of Computational Biochemistry for Elucidating Molecular Mechanisms of Nitric Oxide Synthase.Computational and structural biotechnology journal · 2019Review
- Nitric oxide synthase enzymology in the 20 years after the Nobel Prize.British journal of pharmacology · 2019Review
- A docked state conformational dynamics model to explain the ionic strength dependence of FMN - heme electron transfer in nitric oxide synthase.Journal of inorganic biochemistry · 2018Article
- Role of an isoform-specific residue at the calmodulin-heme (NO synthase) interface in the FMN - heme electron transfer.FEBS letters · 2018Article
- Exploring the conformations of nitric oxide synthase with fluorescence.Frontiers in bioscience (Landmark edition) · 2018Review
- Deciphering mechanism of conformationally controlled electron transfer in nitric oxide synthases.Frontiers in bioscience (Landmark edition) · 2018Review
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Nitric-oxide synthase (NOS) is required in mammals to generate NO for regulating blood pressure, synaptic response, and immune defense. NOS is a large homodimer with well characterized reductase and oxygenase domains that coordinate a multistep, interdomain electron transfer mechanism to oxidize l-arginine and generate NO. Ca(2+)-calmodulin (CaM) binds between the reductase and oxygenase domains to activate NO synthesis. Although NOS has long been proposed to adopt distinct conformations that alternate between interflavin and FMN-heme electron transfer steps, structures of the holoenzyme have remained elusive and the CaM-bound arrangement is unknown. Here we have applied single particle electron microscopy (EM) methods to characterize the full-length of the neuronal isoform (nNOS) complex and determine the structural mechanism of CaM activation. We have identified that nNOS adopts an ensemble of open and closed conformational states and that CaM binding induces a dramatic rearrangement of the reductase domain. Our three-dimensional reconstruction of the intact nNOS-CaM complex reveals a closed conformation and a cross-monomer arrangement with the FMN domain rotated away from the NADPH-FAD center, toward the oxygenase dimer. This work captures, for the first time, the reductase-oxygenase structural arrangement and the CaM-dependent release of the FMN domain that coordinates to drive electron transfer across the domains during catalysis.
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