Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 235 - 244 |
| Number of pages | 10 |
| Journal | Journal of Molecular Recognition |
| Volume | 24 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 2011 |
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Beta-amino acid substitution to investigate the recognition of angiotensin II (AngII) by angiotensin converting enzyme 2 (ACE2). / Clayton, Daniel; Hanchapola, Iresha; Hausler, Nicholas; Unabia, Sharon; Lew, Rebecca A; Widdop, Robert Edward; Smith, Alexander Ian; Perlmutter, Patrick; Aguilar, Marie -Isabel.
In: Journal of Molecular Recognition, Vol. 24, No. 2, 2011, p. 235 - 244.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Beta-amino acid substitution to investigate the recognition of angiotensin II (AngII) by angiotensin converting enzyme 2 (ACE2)
AU - Clayton, Daniel
AU - Hanchapola, Iresha
AU - Hausler, Nicholas
AU - Unabia, Sharon
AU - Lew, Rebecca A
AU - Widdop, Robert Edward
AU - Smith, Alexander Ian
AU - Perlmutter, Patrick
AU - Aguilar, Marie -Isabel
PY - 2011
Y1 - 2011
N2 - In spite of the important role of angiotensin converting enzyme 2 (ACE2) in the cardiovascular system, little is known about the substrate structural requirements of the AngII-ACE2 interaction. Here we investigate how changes in angiotensin II (AngII) structure affect binding and cleavage by ACE2. A series of C3 beta-amino acid AngII analogs were generated and their secondary structure, ACE2 inhibition, and proteolytic stability assessed by circular dichroism (CD), quenched fluorescence substrate (QFS) assay, and LC-MS analysis, respectively. The beta-amino acid-substituted AngII analogs showed differences in secondary structure, ACE2 binding and proteolytic stability. In particular, three different subsets of structure-activity profiles were observed corresponding to substitutions in the N-terminus, the central region and the C-terminal region of AngII. The results show that beta-substitution can dramatically alter the structure of AngII and changes in structure correlated with ACE2 inhibition and/or substrate cleavage. beta-amino acid substitution in the N-terminal region of AngII caused little change in structure or substrate cleavage, while substitution in the central region of AngII lead to increased beta-turn structure and enhanced substrate cleavage. beta-amino acid substitution in the C-terminal region significantly diminished both secondary structure and proteolytic processing by ACE2. The beta-AngII analogs with enhanced or decreased proteolytic stability have potential application for therapeutic intervention in cardiovascular disease.
AB - In spite of the important role of angiotensin converting enzyme 2 (ACE2) in the cardiovascular system, little is known about the substrate structural requirements of the AngII-ACE2 interaction. Here we investigate how changes in angiotensin II (AngII) structure affect binding and cleavage by ACE2. A series of C3 beta-amino acid AngII analogs were generated and their secondary structure, ACE2 inhibition, and proteolytic stability assessed by circular dichroism (CD), quenched fluorescence substrate (QFS) assay, and LC-MS analysis, respectively. The beta-amino acid-substituted AngII analogs showed differences in secondary structure, ACE2 binding and proteolytic stability. In particular, three different subsets of structure-activity profiles were observed corresponding to substitutions in the N-terminus, the central region and the C-terminal region of AngII. The results show that beta-substitution can dramatically alter the structure of AngII and changes in structure correlated with ACE2 inhibition and/or substrate cleavage. beta-amino acid substitution in the N-terminal region of AngII caused little change in structure or substrate cleavage, while substitution in the central region of AngII lead to increased beta-turn structure and enhanced substrate cleavage. beta-amino acid substitution in the C-terminal region significantly diminished both secondary structure and proteolytic processing by ACE2. The beta-AngII analogs with enhanced or decreased proteolytic stability have potential application for therapeutic intervention in cardiovascular disease.
UR - http://www.scopus.com/record/display.url?eid=2-s2.0-79952177776&origin=inward&txGid=feuX03dbM0R2EOQhs7q_WVx%3a15
U2 - 10.1002/jmr.1041
DO - 10.1002/jmr.1041
M3 - Article
VL - 24
SP - 235
EP - 244
JO - Journal of Molecular Recognition
JF - Journal of Molecular Recognition
SN - 0952-3499
IS - 2
ER -