{"id":"a98f283a-e796-5f85-91af-68147f68b128","stable_key":"252872b9-233f-5692-b72b-c8930ba0cfb7:sil-selectivity-is-not-in-the-conserved-residues","predicate":"binds","statement":"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.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"context_dependent","is_public":true,"mechanism_event_id":"18e879d2-f4de-5e81-840f-9db2d22c4422","mechanism_event_label":"The residues it grips are the same ones every enzyme in the family has, so what makes it selective is something else.","subject":{"id":"394ae186-e3c6-5ac8-82c0-8ab9699e75b1","slug":"pde5-catalytic-residues","display_name":"Catalytic domain residues Tyr602, His607, His643 and Asp754 of phosphodiesterase type 5","entity_type_key":"protein_state"},"object":{"id":"fe62cf8d-5f89-5e19-bc36-03ad3c9063b7","slug":"sildenafil","display_name":"Sildenafil","entity_type_key":"drug"},"evidence_count":1,"mechanism_event":{"id":"18e879d2-f4de-5e81-840f-9db2d22c4422","stable_key":"252872b9-233f-5692-b72b-c8930ba0cfb7:sil-selectivity-is-not-in-the-conserved-residues-event","event_type":"biochemical_relationship","label":"The residues it grips are the same ones every enzyme in the family has, so what makes it selective is something else.","description":"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; 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zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf\", \"start_char\": 0, \"end_char\": 1888, \"text_sha256\": \"9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Kinetic and site-directed mutagenesis analysis of inhibitor interaction with the phosphodiesterase type 5 catalytic domain","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Sildenafil, UK-122764 and zaprinast against wild-type enzyme and 23 conserved catalytic-domain point mutants","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"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.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"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.","comparator":null,"unit":null,"notes":"","entity":{"slug":"sildenafil","display_name":"Sildenafil","entity_type_key":"drug"}},{"dimension":"organism","value_text":"Enzyme","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"The residues it grips are the same ones every enzyme in the family has, so what makes it selective is something else.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[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","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Recombinant phosphodiesterase type 5","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"e4657b47-f093-5ceb-964d-934cf489944f","evidence_kind":"source_excerpt","locator":"Lines 171-182","start_line":171,"end_line":182,"excerpt":"### sil-selectivity-is-not-in-the-conserved-residues\nAfter 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.\nCondition category: normal\nnutrient_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.\nplain_language: The residues it grips are the same ones every enzyme in the family has, so what makes it selective is something else.\norganism: Enzyme\ntissue_or_cell_type: Recombinant phosphodiesterase type 5\nexperimental_model: Kinetic and site-directed mutagenesis analysis of inhibitor interaction with the phosphodiesterase type 5 catalytic domain\nlimitations: 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.\nexposure: Sildenafil, UK-122764 and zaprinast against wild-type enzyme and 23 conserved catalytic-domain point mutants\nevidence_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\"}\n[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","model_system":"Kinetic and site-directed mutagenesis analysis of inhibitor interaction with the phosphodiesterase type 5 catalytic domain","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study 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","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"c6c2a590-1f8f-5fac-b2c7-3aae0440b9fd","stable_key":"import-252872b9-233f-5692-b72b-c8930ba0cfb7","title":"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)","document_type":"imported_text","citation_label":"AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text.","file_path":"","sha256":"bc81793d20d20d2eaad9cb530b70695d8d8778a3d7136e24715ac3369b939953","revision_id":"301732e1-2446-5b67-b3bd-580164b85b05","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[],"corrections":[],"research":null}