Cited by 144Hemoglobin structure and functionReceptor Mechanisms and SignalingNitric Oxide and Endothelin Effects

Structure and Activation of Soluble Guanylyl Cyclase, the Nitric Oxide Sensor

Open access
Montfort, William R., Wales, Jessica A., Weichsel, Andrzej·2017·Antioxidants & Redox Signaling

Abstract

Significance: Soluble guanylyl/guanylate cyclase (sGC) is the primary receptor for nitric oxide (NO) and is central to the physiology of blood pressure regulation, wound healing, memory formation, and other key physiological activities. sGC is increasingly implicated in disease and is targeted by novel therapeutic compounds. The protein displays a rich evolutionary history and a fascinating signal transduction mechanism, with NO binding to an N-terminal heme-containing domain, which activates the C-terminal cyclase domains. Recent Advances: Crystal structures of individual sGC domains or their bacterial homologues coupled with small-angle x-ray scattering, electron microscopy, chemical cross-linking, and Förster resonance energy transfer measurements are yielding insight into the overall structure for sGC, which is elongated and likely quite dynamic. Transient kinetic measurements reveal a role for individual domains in lowering NO affinity for heme. New sGC stimulatory drugs are now in the clinic and appear to function through binding near or directly to the sGC heme domain, relieving inhibitory contacts with other domains. New sGC-activating drugs show promise for recovering oxidized sGC in diseases with high inflammation by replacing lost heme. Critical Issues: Despite the many recent advances, sGC regulation, NO activation, and mechanisms of drug binding remain unclear. Here, we describe the molecular evolution of sGC, new molecular models, and the linked equilibria between sGC NO binding, drug binding, and catalytic activity. Future Directions: Recent results and ongoing studies lay the foundation for a complete understanding of structure and mechanism, and they open the door for new drug discovery targeting sGC. Antioxid. Redox Signal . 26, 107–121.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1089/ars.2016.6693

Cites

129 of 129 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Montfort, W. R., Wales, J. A., & Weichsel, A.
Affiliations
University of Arizona (US)
Venue
Antioxidants & Redox Signaling
Published
2017-01
Volume
26
Issue
3
Pages
107-121
ISSN
  • 1523-0864 (ISSN-L)
  • 1557-7716
OpenAlex
W2345952636
Cited by
144
References
129
Citations by year
2026: 9 · 2025: 14 · 2024: 11 · 2023: 14 · 2022: 15 · 2021: 21 · 2020: 14 · 2019: 22 · 2018: 15 · 2017: 6 · 2016: 2
FWCI
1.62
Type
journal article
Language
en
Open access
Locations
  • Antioxidants and Redox Signaling (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Heart Association (P30 CA023074)
  • Ironwood Pharmaceuticals, Incorporated (100003104)
  • National Institutes of Health (CA023074)
  • National Cancer Institute (P30CA023074)
  • National Institute of General Medical Sciences (T32GM008804, R01GM117357)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Keywords
soluble guanylate cyclase, nitric oxide signaling, heme domain, protein structure, sGC activators, protein dynamics, drug discovery
MeSH terms
Soluble Guanylyl Cyclase, Animals, Enzyme Activation, Guanosine Triphosphate, Guanylate Cyclase, Heme, Humans, Models, Molecular, Molecular Conformation, Nitric Oxide, Protein Binding, Structure-Activity Relationship, Signal Transduction, Gene Expression, Protein Subunits, Protein Interaction Domains and Motifs, Drug Discovery

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review