ArticleJournal of the American Chemical Society2010
Heme-coordinating inhibitors of neuronal nitric oxide synthase. Iron-thioether coordination is stabilized by hydrophobic contacts without increased inhibitor potency.
Article in Journal of the American Chemical Society, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
12 citing papers in PubMed, 19 citations in OpenAlex.
- Regulation of nitric oxide generation and consumption.International journal of biological sciences · 2025Review
- Exploring the Potential of Sulfur Moieties in Compounds Inhibiting Steroidogenesis.Biomolecules · 2023Article
- Non-steroidal CYP17A1 Inhibitors: Discovery and Assessment.Journal of medicinal chemistry · 2023Review
- Mechanism of Inactivation of Neuronal Nitric Oxide Synthase by (S)-2-Amino-5-(2-(methylthio)acetimidamido)pentanoic Acid.Journal of the American Chemical Society · 2015Article
- Enzymatic and cryoreduction EPR studies of the hydroxylation of methylated N(ω)-hydroxy-L-arginine analogues by nitric oxide synthase from Geobacillus stearothermophilus.Biochemistry · 2014Article
- Development of nitric oxide synthase inhibitors for neurodegeneration and neuropathic pain.Chemical Society reviews · 2014Review
- Biofragments: an approach towards predicting protein function using biologically related fragments and its application to Mycobacterium tuberculosis CYP126.Chembiochem : a European journal of chemical biology · 2014Article
- Dissecting regulation mechanism of the FMN to heme interdomain electron transfer in nitric oxide synthases.Journal of inorganic biochemistry · 2014Review
- Methylated N(ω)-hydroxy-L-arginine analogues as mechanistic probes for the second step of the nitric oxide synthase-catalyzed reaction.Biochemistry · 2013Article
- Mechanism of Nitric Oxide Synthase Regulation: Electron Transfer and Interdomain Interactions.Coordination chemistry reviews · 2012Article
- Temperature-dependent spin crossover in neuronal nitric oxide synthase bound with the heme-coordinating thioether inhibitors.Journal of the American Chemical Society · 2011Article
- Role of an isoform-specific substrate access channel residue in CO ligand accessibilities of neuronal and inducible nitric oxide synthase isoforms.Biochimica et biophysica acta · 2011Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
The heme-thioether ligand interaction often occurs between heme iron and native methionine ligands, but thioether-based heme-coordinating (type II) inhibitors are uncommon due to the difficulty in stabilizing the Fe-S bond. Here, a thioether-based inhibitor (3) of neuronal nitric oxide synthase (nNOS) was designed, and its binding was characterized by spectrophotometry and crystallography. A crystal structure of inhibitor 3 coordinated to heme iron was obtained, representing, to our knowledge, the first crystal structure of a thioether inhibitor complexed to any heme enzyme. A series of related potential inhibitors (4-8) also were evaluated. Compounds 4-8 were all found to be type I (non-heme-coordinating) inhibitors of ferric nNOS, but 4 and 6-8 were found to switch to type II upon heme reduction to the ferrous state, reflecting the higher affinity of thioethers for ferrous heme than for ferric heme. Contrary to what has been widely thought, thioether-heme ligation was found not to increase inhibitor potency, illustrating the intrinsic weakness of the thioether-ferric heme linkage. Subtle changes in the alkyl groups attached to the thioether sulfur caused drastic changes in the binding conformation, indicating that hydrophobic contacts play a crucial role in stabilizing the thioether-heme coordination.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.