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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
17
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pubmed:dateCreated |
2004-4-19
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pubmed:databankReference |
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pubmed:abstractText |
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-A resolution, respectively. Comparison of these structures revealed a large inhibitor-dependent hinge-bending movement of one catalytic subdomain relative to the other ( approximately 16 degrees ) 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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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Amino Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Carboxypeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Imidazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Leucine,
http://linkedlifedata.com/resource/pubmed/chemical/Peptidyl-Dipeptidase A,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Virus,
http://linkedlifedata.com/resource/pubmed/chemical/Zinc,
http://linkedlifedata.com/resource/pubmed/chemical/angiotensin converting enzyme 2,
http://linkedlifedata.com/resource/pubmed/chemical/coronavirus receptor
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0021-9258
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pubmed:author |
pubmed-author:DalesNatalie ANA,
pubmed-author:FisherMartinM,
pubmed-author:MenonSaurabhS,
pubmed-author:PantolianoMichael WMW,
pubmed-author:ParsonsThomasT,
pubmed-author:PataneMichael AMA,
pubmed-author:PrasadSridhar GSG,
pubmed-author:RyanDominicD,
pubmed-author:StakerBartB,
pubmed-author:TangJinJ,
pubmed-author:TowlerPaulP,
pubmed-author:WilliamsDavidD
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pubmed:issnType |
Print
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pubmed:day |
23
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pubmed:volume |
279
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
17996-8007
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:14754895-Amino Acid Sequence,
pubmed-meshheading:14754895-Amino Acids,
pubmed-meshheading:14754895-Binding Sites,
pubmed-meshheading:14754895-Carboxypeptidases,
pubmed-meshheading:14754895-Catalysis,
pubmed-meshheading:14754895-Crystallography, X-Ray,
pubmed-meshheading:14754895-Enzyme Inhibitors,
pubmed-meshheading:14754895-Humans,
pubmed-meshheading:14754895-Imidazoles,
pubmed-meshheading:14754895-Leucine,
pubmed-meshheading:14754895-Models, Chemical,
pubmed-meshheading:14754895-Models, Molecular,
pubmed-meshheading:14754895-Molecular Sequence Data,
pubmed-meshheading:14754895-Peptidyl-Dipeptidase A,
pubmed-meshheading:14754895-Protein Binding,
pubmed-meshheading:14754895-Protein Conformation,
pubmed-meshheading:14754895-Protein Structure, Tertiary,
pubmed-meshheading:14754895-Receptors, Virus,
pubmed-meshheading:14754895-Sequence Homology, Amino Acid,
pubmed-meshheading:14754895-Substrate Specificity,
pubmed-meshheading:14754895-Zinc
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pubmed:year |
2004
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pubmed:articleTitle |
ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis.
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pubmed:affiliation |
Drug Discovery and Protein Sciences, Millennium Pharmaceuticals, Incorporated, Cambridge, Massachusetts 02139, USA.
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pubmed:publicationType |
Journal Article
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