Catalytic domain residues Tyr602, His607, His643 and Asp754 of phosphodiesterase type 5

What it acts on

1. After site-directed mutagenesis of each of 23 conserved amino acid residues in the catalytic domain, the pattern of changes in inhibitory concentration for sildenafil was most similar to that found for the affinity of cyclic GMP itself, implying similar interactions with the catalytic domain, and residues such as Tyr602, His607, His643 and Asp754 may form important interactions for sildenafil, but because these amino acids are conserved in all mammalian phosphodiesterases the selectivity and potency of the drug is likely to be provided by a nonconserved residue or residues; sildenafil also stimulates cyclic GMP binding to the allosteric sites by interacting at the catalytic site without competing for the allosteric sites themselves.

   Catalytic domain residues Tyr602, His607, His643 and Asp754 of phosphodiesterase type 5 → Sildenafil source_derived_draftungraded
   Experimental context and source evidence

   evidence_span

   {"source_cache": "artifacts/sildenafil-research/10385692.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf", "start_char": 0, "end_char": 1888, "text_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf"}

   experimental_model

   Kinetic and site-directed mutagenesis analysis of inhibitor interaction with the phosphodiesterase type 5 catalytic domain

   exposure

   Sildenafil, UK-122764 and zaprinast against wild-type enzyme and 23 conserved catalytic-domain point mutants

   limitations

   Places the drug at the catalytic site by competition and by a mutant series, and gives the comparison with the natural substrate that makes the affinity meaningful. Recombinant enzyme.

   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 residues it grips are the same ones every enzyme in the family has, so what makes it selective is something else.

   primary_references

   [sil-p10385692] Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds. (1999). https://pubmed.ncbi.nlm.nih.gov/10385692/ DOI: 10.1124/mol.56.1.124

   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 171–182

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Kinetic and site-directed mutagenesis analysis of inhibitor interaction with the phosphodiesterase type 5 catalytic domain · source_derived_draft · unverified_draft

   ### sil-selectivity-is-not-in-the-conserved-residues After site-directed mutagenesis of each of 23 conserved amino acid residues in the catalytic domain, the pattern of changes in inhibitory concentration for sildenafil was most similar to that found for the affinity of cyclic GMP itself, implying similar interactions with the catalytic domain, and residues such as Tyr602, His607, His643 and Asp754 may form important interactions for sildenafil, but because these amino acids are conserved in all mammalian phosphodiesterases the selectivity and potency of the drug is likely to be provided by a nonconserved residue or residues; sildenafil also stimulates cyclic GMP binding to the allosteric sites by interacting at the catalytic site without competing for the allosteric sites themselves. 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 residues it grips are the same ones every enzyme in the family has, so what makes it selective is something else. organism: Enzyme tissue_or_cell_type: Recombinant phosphodiesterase type 5 experimental_model: Kinetic and site-directed mutagenesis analysis of inhibitor interaction with the phosphodiesterase type 5 catalytic domain limitations: Places the drug at the catalytic site by competition and by a mutant series, and gives the comparison with the natural substrate that makes the affinity meaningful. Recombinant enzyme. exposure: Sildenafil, UK-122764 and zaprinast against wild-type enzyme and 23 conserved catalytic-domain point mutants evidence_span: {"source_cache": "artifacts/sildenafil-research/10385692.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf", "start_char": 0, "end_char": 1888, "text_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf"} [sil-p10385692] Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds. (1999). https://pubmed.ncbi.nlm.nih.gov/10385692/ DOI: 10.1124/mol.56.1.124

   Complete structured claim and evidence