Structures of human constitutive nitric oxide synthases
Open accessAbstract
Mammals produce three isoforms of nitric oxide synthase (NOS): neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS). The overproduction of NO by nNOS is associated with a number of neurodegenerative disorders; therefore, a desirable therapeutic goal is the design of drugs that target nNOS but not the other isoforms. Crystallography, coupled with computational approaches and medicinal chemistry, has played a critical role in developing highly selective nNOS inhibitors that exhibit exceptional neuroprotective properties. For historic reasons, crystallography has focused on rat nNOS and bovine eNOS because these were available in high quality; thus, their structures have been used in structure–activity–relationship studies. Although these constitutive NOSs share more than 90% sequence identity across mammalian species for each NOS isoform, inhibitor-binding studies revealed that subtle differences near the heme active site in the same NOS isoform across species still impact enzyme–inhibitor interactions. Therefore, structures of the human constitutive NOSs are indispensible. Here, the first structure of human neuronal NOS at 2.03 Å resolution is reported and a different crystal form of human endothelial NOS is reported at 1.73 Å resolution.
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Production of adequate NO in the vascular endothelium is critical for regulation of blood flow and vasodilation.
“The production of adequate levels of NO in the vascular endothelium is critical for the regulation of blood flow and vasodilation”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [573]
Subsequent progress of the atherosclerotic lesion is dependent on immune cells.
“The current paradigm indicates that macrophage NOX2 is more detrimental in the development of cardiovascular disease (395, 876), with endothelial NOX2 probably involved in the initiation, but not so much in the development of the disease, and a subsequent progress of the atherosclerotic lesion dependent on immune cells (243, 573, 976).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [573]
Endothelial NOX2 is probably involved in the initiation, but not so much in the development of cardiovascular disease.
“The current paradigm indicates that macrophage NOX2 is more detrimental in the development of cardiovascular disease (395, 876), with endothelial NOX2 probably involved in the initiation, but not so much in the development of the disease, and a subsequent progress of the atherosclerotic lesion dependent on immune cells (243, 573, 976).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [573]
NO production is critical for vascular function.
“NO production is critical for vascular function as described in previous sections (299, 573, 600, 786).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [573]
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Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
Tejero, J., Shiva, S., & Gladwin, M. T. (2019) · Physiological Reviews · doi:10.1152/physrev.00036.2017 · Cited by 541 · see citing works
- Authors
- Li, H., Jamal, J., Plaza, C., Pineda, S. H., Chreifi, G., Jing, Q., Cinelli, M. A., Silverman, R. B., & Poulos, T. L.
- Affiliations
- University of California, Irvine (US)
- Northwestern University (US)
- Venue
- Acta Crystallographica Section D Biological Crystallography
- Published
- 2014-09-27
- Volume
- 70
- Issue
- 10
- Pages
- 2667-2674
- ISSN
- 0907-4449 (ISSN-L)
- 1399-0047
- PMC
- PMC4188008
- OpenAlex
- W1969385243
- Cited by
- 45
- References
- 27
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 5 · 2021: 4 · 2020: 7 · 2019: 6 · 2018: 3 · 2017: 7 · 2016: 2 · 2015: 4 · 2014: 1
- FWCI
- 2.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Acta Crystallographica Section D Biological Crystallography (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (GM57353, R01GM057353, GM049725, R01GM049725, F32GM109667)
- Topics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Physical Sciences › Chemistry › Inorganic Chemistry › Crystal structures of chemical compounds
- Keywords
- nitric oxide synthase, neuronal NOS, endothelial NOS, inducible nitric oxide synthase, crystal structure, nNOS inhibitors, structure-activity relationship, heme active site, neuroprotection, nitric oxide
- MeSH terms
- Aminopyridines, Animals, Cattle, Cloning, Molecular, Enzyme Inhibitors, Heme, Humans, Models, Molecular, Pyrrolidines, Protein Structure, Tertiary, Crystallography, X-Ray, Catalytic Domain, Rats, Nitric Oxide Synthase Type I, Nitric Oxide Synthase Type III
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