Structure-activity study of LVV-hemorphin-7: angiotensin AT4 receptor ligand and inhibitor of insulin-regulated aminopeptidase
The decapeptide LVV-hemorphin-7 binds with high affinity to the angiotensin IV (Ang IV) receptor (AT(4) receptor), eliciting a number of physiological effects, including cellular proliferation and memory enhancement. We have recently shown that the AT(4) receptor is identical to insulin-regulated am...
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| Vydáno v: | The Journal of pharmacology and experimental therapeutics Ročník 305; číslo 1; s. 205 |
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| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
01.04.2003
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| ISSN: | 0022-3565 |
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| Abstract | The decapeptide LVV-hemorphin-7 binds with high affinity to the angiotensin IV (Ang IV) receptor (AT(4) receptor), eliciting a number of physiological effects, including cellular proliferation and memory enhancement. We have recently shown that the AT(4) receptor is identical to insulin-regulated aminopeptidase (IRAP) and that both LVV-hemorphin-7 and Ang IV inhibit the catalytic activity of IRAP. In the current study, a series of alanine-substituted and N- or C-terminally modified analogs of LVV-hemorphin-7 were evaluated for their abilities to compete for (125)I-Ang IV binding in sheep adrenal and cerebellar membranes. Selected analogs were also analyzed for binding to recombinant human IRAP and inhibition of IRAP aminopeptidase activity. C-Terminal deletions of LVV-hemorphin-7 resulted in modest changes in affinity for IRAP, whereas deletion of the first three N-terminal residues abolished binding. Monosubstitutions of Tyr(4) and Trp(6) with alanine resulted in a 10-fold reduction in affinity. Competition binding studies using recombinant human IRAP demonstrated the same rank order of affinity as obtained for the ovine tissues. All LVV-hemorphin-7 analogs tested, except for Leu-Val-Val-Tyr, inhibit the cleavage of the synthetic substrate, leucine beta-naphthylamide, by IRAP, with K(i) values between 56 and 620 nM. We find that the Val(3) residue is crucial for LVV-hemorphin-7 binding to IRAP, whereas the C-terminal domain seems to play a minor role. The current study highlights the minimal residues necessary for binding and inhibition of IRAP and provides a basis to design peptidomimetic analogs for experimental and potentially clinical use. |
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| AbstractList | The decapeptide LVV-hemorphin-7 binds with high affinity to the angiotensin IV (Ang IV) receptor (AT(4) receptor), eliciting a number of physiological effects, including cellular proliferation and memory enhancement. We have recently shown that the AT(4) receptor is identical to insulin-regulated aminopeptidase (IRAP) and that both LVV-hemorphin-7 and Ang IV inhibit the catalytic activity of IRAP. In the current study, a series of alanine-substituted and N- or C-terminally modified analogs of LVV-hemorphin-7 were evaluated for their abilities to compete for (125)I-Ang IV binding in sheep adrenal and cerebellar membranes. Selected analogs were also analyzed for binding to recombinant human IRAP and inhibition of IRAP aminopeptidase activity. C-Terminal deletions of LVV-hemorphin-7 resulted in modest changes in affinity for IRAP, whereas deletion of the first three N-terminal residues abolished binding. Monosubstitutions of Tyr(4) and Trp(6) with alanine resulted in a 10-fold reduction in affinity. Competition binding studies using recombinant human IRAP demonstrated the same rank order of affinity as obtained for the ovine tissues. All LVV-hemorphin-7 analogs tested, except for Leu-Val-Val-Tyr, inhibit the cleavage of the synthetic substrate, leucine beta-naphthylamide, by IRAP, with K(i) values between 56 and 620 nM. We find that the Val(3) residue is crucial for LVV-hemorphin-7 binding to IRAP, whereas the C-terminal domain seems to play a minor role. The current study highlights the minimal residues necessary for binding and inhibition of IRAP and provides a basis to design peptidomimetic analogs for experimental and potentially clinical use.The decapeptide LVV-hemorphin-7 binds with high affinity to the angiotensin IV (Ang IV) receptor (AT(4) receptor), eliciting a number of physiological effects, including cellular proliferation and memory enhancement. We have recently shown that the AT(4) receptor is identical to insulin-regulated aminopeptidase (IRAP) and that both LVV-hemorphin-7 and Ang IV inhibit the catalytic activity of IRAP. In the current study, a series of alanine-substituted and N- or C-terminally modified analogs of LVV-hemorphin-7 were evaluated for their abilities to compete for (125)I-Ang IV binding in sheep adrenal and cerebellar membranes. Selected analogs were also analyzed for binding to recombinant human IRAP and inhibition of IRAP aminopeptidase activity. C-Terminal deletions of LVV-hemorphin-7 resulted in modest changes in affinity for IRAP, whereas deletion of the first three N-terminal residues abolished binding. Monosubstitutions of Tyr(4) and Trp(6) with alanine resulted in a 10-fold reduction in affinity. Competition binding studies using recombinant human IRAP demonstrated the same rank order of affinity as obtained for the ovine tissues. All LVV-hemorphin-7 analogs tested, except for Leu-Val-Val-Tyr, inhibit the cleavage of the synthetic substrate, leucine beta-naphthylamide, by IRAP, with K(i) values between 56 and 620 nM. We find that the Val(3) residue is crucial for LVV-hemorphin-7 binding to IRAP, whereas the C-terminal domain seems to play a minor role. The current study highlights the minimal residues necessary for binding and inhibition of IRAP and provides a basis to design peptidomimetic analogs for experimental and potentially clinical use. The decapeptide LVV-hemorphin-7 binds with high affinity to the angiotensin IV (Ang IV) receptor (AT(4) receptor), eliciting a number of physiological effects, including cellular proliferation and memory enhancement. We have recently shown that the AT(4) receptor is identical to insulin-regulated aminopeptidase (IRAP) and that both LVV-hemorphin-7 and Ang IV inhibit the catalytic activity of IRAP. In the current study, a series of alanine-substituted and N- or C-terminally modified analogs of LVV-hemorphin-7 were evaluated for their abilities to compete for (125)I-Ang IV binding in sheep adrenal and cerebellar membranes. Selected analogs were also analyzed for binding to recombinant human IRAP and inhibition of IRAP aminopeptidase activity. C-Terminal deletions of LVV-hemorphin-7 resulted in modest changes in affinity for IRAP, whereas deletion of the first three N-terminal residues abolished binding. Monosubstitutions of Tyr(4) and Trp(6) with alanine resulted in a 10-fold reduction in affinity. Competition binding studies using recombinant human IRAP demonstrated the same rank order of affinity as obtained for the ovine tissues. All LVV-hemorphin-7 analogs tested, except for Leu-Val-Val-Tyr, inhibit the cleavage of the synthetic substrate, leucine beta-naphthylamide, by IRAP, with K(i) values between 56 and 620 nM. We find that the Val(3) residue is crucial for LVV-hemorphin-7 binding to IRAP, whereas the C-terminal domain seems to play a minor role. The current study highlights the minimal residues necessary for binding and inhibition of IRAP and provides a basis to design peptidomimetic analogs for experimental and potentially clinical use. |
| Author | Mustafa, Tomris Lew, Rebecca A Mendelsohn, Frederick A O Albiston, Anthony L Chai, Siew Yeen Lee, Joohyung Brennan, Michelle McDowall, Sharon G |
| Author_xml | – sequence: 1 givenname: Joohyung surname: Lee fullname: Lee, Joohyung organization: Howard Florey Institute, University of Melbourne, Parkville, Victoria, Australia – sequence: 2 givenname: Tomris surname: Mustafa fullname: Mustafa, Tomris – sequence: 3 givenname: Sharon G surname: McDowall fullname: McDowall, Sharon G – sequence: 4 givenname: Frederick A O surname: Mendelsohn fullname: Mendelsohn, Frederick A O – sequence: 5 givenname: Michelle surname: Brennan fullname: Brennan, Michelle – sequence: 6 givenname: Rebecca A surname: Lew fullname: Lew, Rebecca A – sequence: 7 givenname: Anthony L surname: Albiston fullname: Albiston, Anthony L – sequence: 8 givenname: Siew Yeen surname: Chai fullname: Chai, Siew Yeen |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/12649370$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | Alanine - genetics Alanine - metabolism Amino Acid Motifs Amino Acid Substitution Aminopeptidases - metabolism Angiotensin Receptor Antagonists Cells, Cultured Drug Interactions Gene Deletion Hemoglobins - chemistry Hemoglobins - genetics Hemoglobins - pharmacology Humans Insulin - pharmacology Interleukin 1 Receptor Antagonist Protein Ligands Peptide Fragments - chemistry Peptide Fragments - genetics Peptide Fragments - pharmacology Peptides - pharmacology Receptors, Angiotensin Recombinant Proteins - metabolism Sialoglycoproteins - metabolism Structure-Activity Relationship |
| Title | Structure-activity study of LVV-hemorphin-7: angiotensin AT4 receptor ligand and inhibitor of insulin-regulated aminopeptidase |
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