PMID: 14754895

 

    Legend: Sugar

Title : ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis

Abstract :

1. The angiotensin-converting enzyme ( ACE ACE)-related carboxypeptidase , ACE2 , is a type I integral membrane protein of 805 amino acids that contains one HEXXH + E zinc-binding consensus sequence
2. 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 )
3. 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
4. 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
5. 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
6. 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