The GAF domain of phosphodiesterase type 5: molecular mechanisms & dependencies

How nutrients influence it

Every nutrient with a recorded effect on this component, credited to the nutrient that acted rather than the chapter that recorded it. Open a nutrient to see the findings and the conditions they were measured under.

Human evidence only

How nutrients reach it in more than one step

Chains of two or more recorded steps that end here, grouped by the nutrient they start from. Each step is a separate finding, so a chain is a route a mechanism could take, not proof that it does.

Tracing routes…

What it does

Every recorded relationship this component is part of, grouped by its role. Plain wording comes first; the technical statement follows.

Recorded relationships

What it acts on

The isolated first GAF domain of phosphodiesterase type 5 binds cyclic GMP with a dissociation constant of 650 nanomolar, the binding site identified by homology modelling and site-directed mutagenesis consisting of conserved arginine, asparagine, lysine and aspartate residues, and the structural and binding studies together show that cyclic GMP binding GAF domains form a new class of cyclic nucleotide receptors distinct from the regulatory domains of cyclic nucleotide-regulated protein kinases and ion channels.
The GAF domain of phosphodiesterase type 5 → Cyclic guanosine monophosphate source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/11032796.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c3fde3e8ef99d45fbe9c59a9f4eba5a696b7e212dd2fc6d23999ce724d2996d9", "start_char": 0, "end_char": 1012, "text_sha256": "c3fde3e8ef99d45fbe9c59a9f4eba5a696b7e212dd2fc6d23999ce724d2996d9"}
experimental_model
Crystal structure of a GAF domain at 1.9 angstrom with homology modelling and mutagenesis of the phosphodiesterase type 5 domain
exposure
Cyclic GMP binding to the isolated first GAF domain of phosphodiesterase type 5
limitations
A structure of a related domain plus modelling rather than a structure of the phosphodiesterase domain itself. The binding constant is measured directly.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Yeast and human protein
plain_language
The regulatory half of the enzyme is itself a receptor for the messenger it destroys.
primary_references
[sil-p11032796] Structure of the GAF domain, a ubiquitous signaling motif and a new class of cyclic GMP receptor. (2000). https://pubmed.ncbi.nlm.nih.gov/11032796/ DOI: 10.1093/emboj/19.20.5288
tissue_or_cell_type
GAF domain
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 223–234
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crystal structure of a GAF domain at 1.9 angstrom with homology modelling and mutagenesis of the phosphodiesterase type 5 domain · source_derived_draft · unverified_draft
### sil-gaf-is-a-nucleotide-receptor The isolated first GAF domain of phosphodiesterase type 5 binds cyclic GMP with a dissociation constant of 650 nanomolar, the binding site identified by homology modelling and site-directed mutagenesis consisting of conserved arginine, asparagine, lysine and aspartate residues, and the structural and binding studies together show that cyclic GMP binding GAF domains form a new class of cyclic nucleotide receptors distinct from the regulatory domains of cyclic nucleotide-regulated protein kinases and ion channels. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The regulatory half of the enzyme is itself a receptor for the messenger it destroys. organism: Yeast and human protein tissue_or_cell_type: GAF domain experimental_model: Crystal structure of a GAF domain at 1.9 angstrom with homology modelling and mutagenesis of the phosphodiesterase type 5 domain limitations: A structure of a related domain plus modelling rather than a structure of the phosphodiesterase domain itself. The binding constant is measured directly. exposure: Cyclic GMP binding to the isolated first GAF domain of phosphodiesterase type 5 evidence_span: {"source_cache": "artifacts/sildenafil-research/11032796.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c3fde3e8ef99d45fbe9c59a9f4eba5a696b7e212dd2fc6d23999ce724d2996d9", "start_char": 0, "end_char": 1012, "text_sha256": "c3fde3e8ef99d45fbe9c59a9f4eba5a696b7e212dd2fc6d23999ce724d2996d9"} [sil-p11032796] Structure of the GAF domain, a ubiquitous signaling motif and a new class of cyclic GMP receptor. (2000). https://pubmed.ncbi.nlm.nih.gov/11032796/ DOI: 10.1093/emboj/19.20.5288
Complete structured claim and evidence

Where it participates (unsigned role)

Mutations affecting cyclic GMP binding to either one or both allosteric sites of phosphodiesterase type 5 do not influence cyclic GMP hydrolysis at the catalytic site under the conditions used, but the mutants defective in binding at either site require much higher cyclic GMP concentrations for allosteric stimulation of phosphorylation, while a mutant with higher binding affinity is phosphorylated at lower cyclic GMP concentrations, so binding to the allosteric sites does not directly affect catalysis but regulates phosphorylation of the enzyme.
The two tandem allosteric cyclic GMP binding sites of phosphodiesterase type 5 → Phosphodiesterase type 5 phosphorylated at serine 92 source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/9445376.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f59d258bd35b229b3455ab2d15e1d21fbe5a475a1b936ecd423eb49c9a9aea29", "start_char": 0, "end_char": 1541, "text_sha256": "f59d258bd35b229b3455ab2d15e1d21fbe5a475a1b936ecd423eb49c9a9aea29"}
experimental_model
Site-directed mutagenesis of the two tandem allosteric cyclic GMP binding sites of phosphodiesterase type 5
exposure
D289A, D478A and D289A/D478A binding-site mutants, with phosphorylation by the catalytic subunit of cyclic AMP-dependent protein kinase
limitations
Separates what the allosteric sites do from what the catalytic site does, using mutants that lose binding at one site, the other, or both.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Enzyme
plain_language
The second pair of binding sites does not change how fast the enzyme works; it decides when the enzyme gets switched up.
primary_references
[sil-p9445376] Binding of cGMP to both allosteric sites of cGMP-binding cGMP-specific phosphodiesterase (PDE5) is required for its phosphorylation. (1998). https://pubmed.ncbi.nlm.nih.gov/9445376/ DOI: 10.1042/bj3290505
tissue_or_cell_type
Recombinant phosphodiesterase type 5
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 184–195
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Site-directed mutagenesis of the two tandem allosteric cyclic GMP binding sites of phosphodiesterase type 5 · source_derived_draft · unverified_draft
### sil-allosteric-sites-gate-phosphorylation Mutations affecting cyclic GMP binding to either one or both allosteric sites of phosphodiesterase type 5 do not influence cyclic GMP hydrolysis at the catalytic site under the conditions used, but the mutants defective in binding at either site require much higher cyclic GMP concentrations for allosteric stimulation of phosphorylation, while a mutant with higher binding affinity is phosphorylated at lower cyclic GMP concentrations, so binding to the allosteric sites does not directly affect catalysis but regulates phosphorylation of the enzyme. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The second pair of binding sites does not change how fast the enzyme works; it decides when the enzyme gets switched up. organism: Enzyme tissue_or_cell_type: Recombinant phosphodiesterase type 5 experimental_model: Site-directed mutagenesis of the two tandem allosteric cyclic GMP binding sites of phosphodiesterase type 5 limitations: Separates what the allosteric sites do from what the catalytic site does, using mutants that lose binding at one site, the other, or both. exposure: D289A, D478A and D289A/D478A binding-site mutants, with phosphorylation by the catalytic subunit of cyclic AMP-dependent protein kinase evidence_span: {"source_cache": "artifacts/sildenafil-research/9445376.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f59d258bd35b229b3455ab2d15e1d21fbe5a475a1b936ecd423eb49c9a9aea29", "start_char": 0, "end_char": 1541, "text_sha256": "f59d258bd35b229b3455ab2d15e1d21fbe5a475a1b936ecd423eb49c9a9aea29"} [sil-p9445376] Binding of cGMP to both allosteric sites of cGMP-binding cGMP-specific phosphodiesterase (PDE5) is required for its phosphorylation. (1998). https://pubmed.ncbi.nlm.nih.gov/9445376/ DOI: 10.1042/bj3290505
Complete structured claim and evidence

The events it takes part in

A mechanism often involves more than two components. These are the full events, with every participant and its role.

Situations it appears in

Low-supply and faulty-machinery situations recorded in the chapters where this component plays a part.

In the sources

Preserved passages that mention this component, quoted exactly. Open one to read it in context.

Open hypotheses

Proposed ideas that involve this component. They are labeled as hypotheses and do not change any recorded statement.

This is a research prototype built from draft material. It is not medical advice, and its statements still await verification against the original studies.

The GAF domain of phosphodiesterase type 5