Structural determinants for binding to angiotensin converting enzyme 2 (ACE2) and angiotensin receptors
Angiotensin converting enzyme 2 (ACE2) is a zinc carboxypeptidase involved in the renin angiotensin system (RAS) and inactivates the potent vasopressive peptide angiotensin II (Ang II) by removing the C-terminal phenylalanine residue to yield Ang1-7. This conversion inactivates the vasoconstrictive...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2015-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fphar.2015.00005/full |
| _version_ | 1831667005716955136 |
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| author | Daniel eClayton Iresha eHanchapola Walter Glen Thomas Robert eWiddop Alexander Ian Smith Patrick ePerlmutter Marie-Isabel eAguilar |
| author_facet | Daniel eClayton Iresha eHanchapola Walter Glen Thomas Robert eWiddop Alexander Ian Smith Patrick ePerlmutter Marie-Isabel eAguilar |
| author_sort | Daniel eClayton |
| collection | DOAJ |
| description | Angiotensin converting enzyme 2 (ACE2) is a zinc carboxypeptidase involved in the renin angiotensin system (RAS) and inactivates the potent vasopressive peptide angiotensin II (Ang II) by removing the C-terminal phenylalanine residue to yield Ang1-7. This conversion inactivates the vasoconstrictive action of Ang II and yields a peptide that acts as a vasodilatory molecule at the Mas receptor and potentially other receptors. Given the growing complexity of RAS and level of cross-talk between ligands and their corresponding enzymes and receptors, the design of molecules with selectivity for the major RAS binding partners to control cardiovascular tone is an on-going challenge. In previous studies we used single β-amino acid substitutions to modulate the structure of Ang II and its selectivity for ACE2, AT1R and angiotensin type 2 (AT2R) receptor. We showed that modification at the C-terminus of Ang II generally resulted in more pronounced changes to secondary structure and ligand binding, and here we further explore this region for the potential to modulate ligand specificity. In this study, 1) a library of forty-seven peptides derived from the C-terminal tetra-peptide sequence (-IHPF) of Ang II was synthesised and assessed for ACE2 binding, 2) the terminal group requirements for high affinity ACE2 binding were explored by and N- and C-terminal modification, 3) high affinity ACE2 binding chimeric AngII analogues were then synthesized and assessed, 4) the structure of the full-length Ang II analogues were assessed by circular dichroism, and 5) the Ang II analogues were assessed for AT1R/AT2R selectivity by cell-based assays. Studies on the C-terminus of Ang II demonstrated varied specificity at different residue positions for ACE2 binding and four Ang II chimeric peptides were identified as selective ligands for the AT2 receptor. Overall, these results provide insight into the residue and structural requirements for ACE2 binding and angiotensin receptor selectivity. |
| first_indexed | 2024-12-19T20:03:08Z |
| format | Article |
| id | doaj.art-56f1b230a179477886fde8c3f21d1110 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-19T20:03:08Z |
| publishDate | 2015-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-56f1b230a179477886fde8c3f21d11102022-12-21T20:07:35ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122015-01-01610.3389/fphar.2015.00005128514Structural determinants for binding to angiotensin converting enzyme 2 (ACE2) and angiotensin receptorsDaniel eClayton0Iresha eHanchapola1Walter Glen Thomas2Robert eWiddop3Alexander Ian Smith4Patrick ePerlmutter5Marie-Isabel eAguilar6Monash UniversityMonash UniversityUnivesity of QuuenslandMonash UniversityMonash UniversityMonash UniversityMonash UniversityAngiotensin converting enzyme 2 (ACE2) is a zinc carboxypeptidase involved in the renin angiotensin system (RAS) and inactivates the potent vasopressive peptide angiotensin II (Ang II) by removing the C-terminal phenylalanine residue to yield Ang1-7. This conversion inactivates the vasoconstrictive action of Ang II and yields a peptide that acts as a vasodilatory molecule at the Mas receptor and potentially other receptors. Given the growing complexity of RAS and level of cross-talk between ligands and their corresponding enzymes and receptors, the design of molecules with selectivity for the major RAS binding partners to control cardiovascular tone is an on-going challenge. In previous studies we used single β-amino acid substitutions to modulate the structure of Ang II and its selectivity for ACE2, AT1R and angiotensin type 2 (AT2R) receptor. We showed that modification at the C-terminus of Ang II generally resulted in more pronounced changes to secondary structure and ligand binding, and here we further explore this region for the potential to modulate ligand specificity. In this study, 1) a library of forty-seven peptides derived from the C-terminal tetra-peptide sequence (-IHPF) of Ang II was synthesised and assessed for ACE2 binding, 2) the terminal group requirements for high affinity ACE2 binding were explored by and N- and C-terminal modification, 3) high affinity ACE2 binding chimeric AngII analogues were then synthesized and assessed, 4) the structure of the full-length Ang II analogues were assessed by circular dichroism, and 5) the Ang II analogues were assessed for AT1R/AT2R selectivity by cell-based assays. Studies on the C-terminus of Ang II demonstrated varied specificity at different residue positions for ACE2 binding and four Ang II chimeric peptides were identified as selective ligands for the AT2 receptor. Overall, these results provide insight into the residue and structural requirements for ACE2 binding and angiotensin receptor selectivity.http://journal.frontiersin.org/Journal/10.3389/fphar.2015.00005/fullAngiotensin IIAngiotensin II receptor 1Angiotensin converting enzyme-2angiotensin II receptor 2-amino acids |
| spellingShingle | Daniel eClayton Iresha eHanchapola Walter Glen Thomas Robert eWiddop Alexander Ian Smith Patrick ePerlmutter Marie-Isabel eAguilar Structural determinants for binding to angiotensin converting enzyme 2 (ACE2) and angiotensin receptors Frontiers in Pharmacology Angiotensin II Angiotensin II receptor 1 Angiotensin converting enzyme-2 angiotensin II receptor 2 -amino acids |
| title | Structural determinants for binding to angiotensin converting enzyme 2 (ACE2) and angiotensin receptors |
| title_full | Structural determinants for binding to angiotensin converting enzyme 2 (ACE2) and angiotensin receptors |
| title_fullStr | Structural determinants for binding to angiotensin converting enzyme 2 (ACE2) and angiotensin receptors |
| title_full_unstemmed | Structural determinants for binding to angiotensin converting enzyme 2 (ACE2) and angiotensin receptors |
| title_short | Structural determinants for binding to angiotensin converting enzyme 2 (ACE2) and angiotensin receptors |
| title_sort | structural determinants for binding to angiotensin converting enzyme 2 ace2 and angiotensin receptors |
| topic | Angiotensin II Angiotensin II receptor 1 Angiotensin converting enzyme-2 angiotensin II receptor 2 -amino acids |
| url | http://journal.frontiersin.org/Journal/10.3389/fphar.2015.00005/full |
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