ArticleBiochemistry2014
The mobility of a conserved tyrosine residue controls isoform-dependent enzyme-inhibitor interactions in nitric oxide synthases.
Article in Biochemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 29 citations in OpenAlex.
- Combined Anti-Inflammatory Effects of Curcumin and Evodiamine: In Vitro Synergy, Docking, and Molecular Orbital Insights.International journal of molecular sciences · 2026Article
- Glutathione responsive iNOS inhibiting polymeric prodrug for targeted Inhibition of angiogenesis.Journal of nanobiotechnology · 2026Article
- Crystallographic and Computational Insights into Isoform-Selective Dynamics in Nitric Oxide Synthase.Biochemistry · 2024Article
- Isolation, Identification, Anti-Inflammatory, and In Silico Analysis of New Lignans from the Resin ofPharmaceuticals (Basel, Switzerland) · 2023Article
- Insights into human eNOS, nNOS and iNOS structures and medicinal indications from statistical analyses of their interactions with bound compounds.Biophysics reports · 2023Article
- Nitric oxide synthase and its function in animal reproduction: an update.Frontiers in physiology · 2023Review
- Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors.Journal of medicinal chemistry · 2017Article
- Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2-Aminopyridine-Based Scaffold with a Pyridine Linker.Journal of medicinal chemistry · 2016Article
- Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase.Journal of medicinal chemistry · 2015Article
- Fluorination Effects on NOS Inhibitory Activity of Pyrazoles Related to Curcumin.Molecules (Basel, Switzerland) · 2015Article
- 2-Aminopyridines with a Truncated Side Chain To Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity.Journal of medicinal chemistry · 2015Article
- Inhibitor Bound Crystal Structures of Bacterial Nitric Oxide Synthase.Biochemistry · 2015Article
- Nitric Oxide Synthase as a Target for Methicillin-Resistant Staphylococcus aureus.Chemistry & biology · 2015Article
- Novel 2,4-disubstituted pyrimidines as potent, selective, and cell-permeable inhibitors of neuronal nitric oxide synthase.Journal of medicinal chemistry · 2015Article
- Structures of human constitutive nitric oxide synthases.Acta crystallographica. Section D, Biological crystallography · 2014Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
Many pyrrolidine-based inhibitors highly selective for neuronal nitric oxide synthase (nNOS) over endothelial NOS (eNOS) exhibit dramatically different binding modes. In some cases, the inhibitor binds in a 180° flipped orientation in nNOS relative to eNOS. From the several crystal structures we have determined, we know that isoform selectivity correlates with the rotamer position of a conserved tyrosine residue that H-bonds with a heme propionate. In nNOS, this Tyr more readily adopts the out-rotamer conformation, while in eNOS, the Tyr tends to remain fixed in the original in-rotamer conformation. In the out-rotamer conformation, inhibitors are able to form better H-bonds with the protein and heme, thus increasing inhibitor potency. A segment of polypeptide that runs along the surface near the conserved Tyr has long been thought to be the reason for the difference in Tyr mobility. Although this segment is usually disordered in both eNOS and nNOS, sequence comparisons and modeling from a few structures show that this segment is structured quite differently in eNOS and nNOS. In this study, we have probed the importance of this surface segment near the Tyr by making a few mutants in the region followed by crystal structure determinations. In addition, because the segment near the conserved Tyr is highly ordered in iNOS, we also determined the structure of an iNOS-inhibitor complex. This new structure provides further insight into the critical role that mobility plays in isoform selectivity.
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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.