FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W1991231974> ?p ?o ?g. }

• W1991231974 endingPage "5939" @default.
• W1991231974 startingPage "5929" @default.
• W1991231974 abstract "Cytochrome P450 (P450) 3A4 is the most abundant human P450 enzyme and has broad selectivity for substrates. The enzyme can show marked catalytic regioselectivity and unusual patterns of homotropic and heterotropic cooperativity, for which several models have been proposed. Spectral titration studies indicated one binding site for the drug indinavir (M(r) 614), a known substrate and inhibitor. Several C-terminal aminated peptides, including the model morphiceptin (YPFP-NH(2)), bind with spectral changes indicative of Fe-NH(2) bonding. The binding of the YPFP-NH(2) N-terminal amine and the influence of C-terminal modification on binding argue that the entire molecule (M(r) 521) fits within P450 3A4. YPFP-NH(2) was not oxidized by P450 3A4 but blocked binding of the substrates testosterone and midazolam, with K(i) values similar to the spectral binding constant (K(s)) for YPFP-NH(2). YPFP-NH(2) inhibited the oxidations of several typical P450 substrates with K(i) values 10-fold greater than the K(s) for binding YPFP-NH(2) and its K(i) for inhibiting substrate binding. The n values for cooperativity of these oxidations were not altered by YPFP-NH(2). YPFP-NH(2) inhibited the oxidations of midazolam at two different positions (1'- and 4-) with 20-fold different K(i) values. The differences in the K(i) values for blocking the binding to ferric P450 3A4 and the oxidation of several substrates may be attributed to weaker binding of YPFP-NH(2) to ferrous P450 3A4 than to the ferric form. The ferrous protein can be considered a distinct form of the enzyme in binding and catalysis because many substrates (but not YPFP-NH(2)) facilitate reduction of the ferric to ferrous enzyme. Our results with these peptides are considered in the context of several proposed models. A P450 3A4 model based on these peptide studies contains at least two and probably three distinct ligand sites, with testosterone and alpha-naphthoflavone occupying distinct sites. Midazolam appears to be able to bind to P450 3A4 in two modes, one corresponding to the testosterone binding mode and one postulated to reflect binding in a third site, distinct from both testosterone and alpha-naphthoflavone. The work with indinavir and YPFP-NH(2) also argues that room should be present in P450 3A4 to bind more than one smaller ligand in the testosterone site, although no direct evidence for such binding exists. Although this work with peptides provides evidence for the existence of multiple ligand binding sites, the results cannot be used to indicate their juxtaposition, which may vary through the catalytic cycle." @default.
• W1991231974 created "2016-06-24" @default.
• W1991231974 creator A5013945168 @default.
• W1991231974 creator A5045303959 @default.
• W1991231974 creator A5058389506 @default.
• W1991231974 date "2000-04-19" @default.
• W1991231974 modified "2023-10-08" @default.
• W1991231974 title "Elucidation of Distinct Ligand Binding Sites for Cytochrome P450 3A4" @default.
• W1991231974 cites W1509690851 @default.
• W1991231974 cites W1520965071 @default.
• W1991231974 cites W1532212858 @default.
• W1991231974 cites W1582917959 @default.
• W1991231974 cites W1588708623 @default.
• W1991231974 cites W1606334243 @default.
• W1991231974 cites W1989852001 @default.
• W1991231974 cites W2045307713 @default.
• W1991231974 cites W2053623537 @default.
• W1991231974 cites W2055370562 @default.
• W1991231974 cites W2059293500 @default.
• W1991231974 cites W2061734875 @default.
• W1991231974 cites W2087583457 @default.
• W1991231974 cites W2089763284 @default.
• W1991231974 cites W2093548859 @default.
• W1991231974 cites W2147981987 @default.
• W1991231974 cites W2150946709 @default.
• W1991231974 cites W4235111215 @default.
• W1991231974 doi "https://doi.org/10.1021/bi992765t" @default.
• W1991231974 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/10821664" @default.
• W1991231974 hasPublicationYear "2000" @default.
• W1991231974 type Work @default.
• W1991231974 sameAs 1991231974 @default.
• W1991231974 citedByCount "210" @default.
• W1991231974 countsByYear W19912319742012 @default.
• W1991231974 countsByYear W19912319742013 @default.
• W1991231974 countsByYear W19912319742014 @default.
• W1991231974 countsByYear W19912319742015 @default.
• W1991231974 countsByYear W19912319742016 @default.
• W1991231974 countsByYear W19912319742017 @default.
• W1991231974 countsByYear W19912319742018 @default.
• W1991231974 countsByYear W19912319742019 @default.
• W1991231974 countsByYear W19912319742020 @default.
• W1991231974 countsByYear W19912319742021 @default.
• W1991231974 countsByYear W19912319742022 @default.
• W1991231974 countsByYear W19912319742023 @default.
• W1991231974 crossrefType "journal-article" @default.
• W1991231974 hasAuthorship W1991231974A5013945168 @default.
• W1991231974 hasAuthorship W1991231974A5045303959 @default.
• W1991231974 hasAuthorship W1991231974A5058389506 @default.
• W1991231974 hasConcept C107824862 @default.
• W1991231974 hasConcept C111368507 @default.
• W1991231974 hasConcept C127313418 @default.
• W1991231974 hasConcept C166014724 @default.
• W1991231974 hasConcept C181199279 @default.
• W1991231974 hasConcept C185592680 @default.
• W1991231974 hasConcept C187250156 @default.
• W1991231974 hasConcept C2777289219 @default.
• W1991231974 hasConcept C2780283098 @default.
• W1991231974 hasConcept C526171541 @default.
• W1991231974 hasConcept C55493867 @default.
• W1991231974 hasConcept C71240020 @default.
• W1991231974 hasConceptScore W1991231974C107824862 @default.
• W1991231974 hasConceptScore W1991231974C111368507 @default.
• W1991231974 hasConceptScore W1991231974C127313418 @default.
• W1991231974 hasConceptScore W1991231974C166014724 @default.
• W1991231974 hasConceptScore W1991231974C181199279 @default.
• W1991231974 hasConceptScore W1991231974C185592680 @default.
• W1991231974 hasConceptScore W1991231974C187250156 @default.
• W1991231974 hasConceptScore W1991231974C2777289219 @default.
• W1991231974 hasConceptScore W1991231974C2780283098 @default.
• W1991231974 hasConceptScore W1991231974C526171541 @default.
• W1991231974 hasConceptScore W1991231974C55493867 @default.
• W1991231974 hasConceptScore W1991231974C71240020 @default.
• W1991231974 hasIssue "20" @default.
• W1991231974 hasLocation W19912319741 @default.
• W1991231974 hasLocation W19912319742 @default.
• W1991231974 hasOpenAccess W1991231974 @default.
• W1991231974 hasPrimaryLocation W19912319741 @default.
• W1991231974 hasRelatedWork W1004292963 @default.
• W1991231974 hasRelatedWork W1965064962 @default.
• W1991231974 hasRelatedWork W1986169335 @default.
• W1991231974 hasRelatedWork W1997135566 @default.
• W1991231974 hasRelatedWork W2067253151 @default.
• W1991231974 hasRelatedWork W2075856071 @default.
• W1991231974 hasRelatedWork W2078068721 @default.
• W1991231974 hasRelatedWork W3174779094 @default.
• W1991231974 hasRelatedWork W4205106225 @default.
• W1991231974 hasRelatedWork W2092615839 @default.
• W1991231974 hasVolume "39" @default.
• W1991231974 isParatext "false" @default.
• W1991231974 isRetracted "false" @default.
• W1991231974 magId "1991231974" @default.
• W1991231974 workType "article" @default.