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ACE2 X-Ray Structures Reveal a Large Hinge-bending Motion Important for Inhibitor Binding and Catalysis

The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE2, is a type I integral membrane protein of 805 amino acids that contains one HEXXH + E zinc-binding consensus sequence. ACE2 has been implicated in the regulation of heart function and also as a functional receptor for the coronav...

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Autores principales: Towler, Paul, Staker, Bart, Prasad, Sridhar G., Menon, Saurabh, Tang, Jin, Parsons, Thomas, Ryan, Dominic, Fisher, Martin, Williams, David, Dales, Natalie A., Patane, Michael A., Pantoliano, Michael W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. 2004
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980034/
https://www.ncbi.nlm.nih.gov/pubmed/14754895
http://dx.doi.org/10.1074/jbc.M311191200
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author Towler, Paul
Staker, Bart
Prasad, Sridhar G.
Menon, Saurabh
Tang, Jin
Parsons, Thomas
Ryan, Dominic
Fisher, Martin
Williams, David
Dales, Natalie A.
Patane, Michael A.
Pantoliano, Michael W.
author_facet Towler, Paul
Staker, Bart
Prasad, Sridhar G.
Menon, Saurabh
Tang, Jin
Parsons, Thomas
Ryan, Dominic
Fisher, Martin
Williams, David
Dales, Natalie A.
Patane, Michael A.
Pantoliano, Michael W.
author_sort Towler, Paul
collection PubMed
description The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE2, is a type I integral membrane protein of 805 amino acids that contains one HEXXH + E zinc-binding consensus sequence. ACE2 has been implicated in the regulation of heart function and also as a functional receptor for the coronavirus that causes the severe acute respiratory syndrome (SARS). To gain further insights into this enzyme, the first crystal structures of the native and inhibitor-bound forms of the ACE2 extracellular domains were solved to 2.2- and 3.0-Å resolution, respectively. Comparison of these structures revealed a large inhibitor-dependent hinge-bending movement of one catalytic subdomain relative to the other (∼16°) that brings important residues into position for catalysis. The potent inhibitor MLN-4760 ((S,S)-2-{1-carboxy-2-[3-(3,5-dichlorobenzyl)-3H-imidazol4-yl]-ethylamino}-4-methylpentanoic acid) makes key binding interactions within the active site and offers insights regarding the action of residues involved in catalysis and substrate specificity. A few active site residue substitutions in ACE2 relative to ACE appear to eliminate the S(2)′ substrate-binding subsite and account for the observed reactivity change from the peptidyl dipeptidase activity of ACE to the carboxypeptidase activity of ACE2.
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spelling pubmed-79800342021-03-23 ACE2 X-Ray Structures Reveal a Large Hinge-bending Motion Important for Inhibitor Binding and Catalysis Towler, Paul Staker, Bart Prasad, Sridhar G. Menon, Saurabh Tang, Jin Parsons, Thomas Ryan, Dominic Fisher, Martin Williams, David Dales, Natalie A. Patane, Michael A. Pantoliano, Michael W. J Biol Chem Protein Structure and Folding The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE2, is a type I integral membrane protein of 805 amino acids that contains one HEXXH + E zinc-binding consensus sequence. ACE2 has been implicated in the regulation of heart function and also as a functional receptor for the coronavirus that causes the severe acute respiratory syndrome (SARS). To gain further insights into this enzyme, the first crystal structures of the native and inhibitor-bound forms of the ACE2 extracellular domains were solved to 2.2- and 3.0-Å resolution, respectively. Comparison of these structures revealed a large inhibitor-dependent hinge-bending movement of one catalytic subdomain relative to the other (∼16°) that brings important residues into position for catalysis. The potent inhibitor MLN-4760 ((S,S)-2-{1-carboxy-2-[3-(3,5-dichlorobenzyl)-3H-imidazol4-yl]-ethylamino}-4-methylpentanoic acid) makes key binding interactions within the active site and offers insights regarding the action of residues involved in catalysis and substrate specificity. A few active site residue substitutions in ACE2 relative to ACE appear to eliminate the S(2)′ substrate-binding subsite and account for the observed reactivity change from the peptidyl dipeptidase activity of ACE to the carboxypeptidase activity of ACE2. ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. 2004-04-23 2021-01-04 /pmc/articles/PMC7980034/ /pubmed/14754895 http://dx.doi.org/10.1074/jbc.M311191200 Text en © 2004 © 2004 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Protein Structure and Folding
Towler, Paul
Staker, Bart
Prasad, Sridhar G.
Menon, Saurabh
Tang, Jin
Parsons, Thomas
Ryan, Dominic
Fisher, Martin
Williams, David
Dales, Natalie A.
Patane, Michael A.
Pantoliano, Michael W.
ACE2 X-Ray Structures Reveal a Large Hinge-bending Motion Important for Inhibitor Binding and Catalysis
title ACE2 X-Ray Structures Reveal a Large Hinge-bending Motion Important for Inhibitor Binding and Catalysis
title_full ACE2 X-Ray Structures Reveal a Large Hinge-bending Motion Important for Inhibitor Binding and Catalysis
title_fullStr ACE2 X-Ray Structures Reveal a Large Hinge-bending Motion Important for Inhibitor Binding and Catalysis
title_full_unstemmed ACE2 X-Ray Structures Reveal a Large Hinge-bending Motion Important for Inhibitor Binding and Catalysis
title_short ACE2 X-Ray Structures Reveal a Large Hinge-bending Motion Important for Inhibitor Binding and Catalysis
title_sort ace2 x-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis
topic Protein Structure and Folding
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980034/
https://www.ncbi.nlm.nih.gov/pubmed/14754895
http://dx.doi.org/10.1074/jbc.M311191200
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