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

J Biol Chem. 2004 Apr 23;279(17):17996-8007. doi: 10.1074/jbc.M311191200. Epub 2004 Jan 30.


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.

MeSH terms

  • Amino Acid Sequence
  • Amino Acids / chemistry
  • Angiotensin-Converting Enzyme 2
  • Binding Sites
  • Carboxypeptidases / chemistry*
  • Catalysis
  • Crystallography, X-Ray
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Imidazoles / pharmacology
  • Leucine / analogs & derivatives
  • Leucine / pharmacology
  • Models, Chemical
  • Models, Molecular
  • Molecular Sequence Data
  • Peptidyl-Dipeptidase A
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Receptors, Coronavirus
  • Receptors, Virus / chemistry
  • Sequence Homology, Amino Acid
  • Substrate Specificity
  • Zinc / chemistry


  • 2-(1-carboxy-2-(3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl)ethylamino)-4-methylpentanoic acid
  • Amino Acids
  • Enzyme Inhibitors
  • Imidazoles
  • Receptors, Coronavirus
  • Receptors, Virus
  • Carboxypeptidases
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • Leucine
  • Zinc

Associated data

  • PDB/1R42
  • PDB/1R4L