Crystal structures of native and inhibitor-bound ACE2 reveal a 16-degree hinge-bending movement upon binding of the inhibitor MLN-4760, bringing key residues into position for catalysis.
The first crystal structures of ACE2 reveal a large hinge-bending motion upon inhibitor binding, providing insights into its catalytic mechanism and substrate specificity.
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.
Towler et al. (Thu,) reported a other. MLN-4760 vs. Native ACE2 was evaluated. Crystal structures of native and inhibitor-bound ACE2 reveal a 16-degree hinge-bending movement upon binding of the inhibitor MLN-4760, bringing key residues into position for catalysis.