title: ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis.
abstract: 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.
authors.affiliation: Drug Discovery and Protein Sciences, Millennium Pharmaceuticals, Incorporated, Cambridge, Massachusetts 02139, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Towler
authors.forename: Bart
authors.initials: B
authors.lastname: Staker
authors.forename: Sridhar G
authors.initials: SG
authors.lastname: Prasad
authors.forename: Saurabh
authors.initials: S
authors.lastname: Menon
authors.forename: Jin
authors.initials: J
authors.lastname: Tang
authors.forename: Thomas
authors.initials: T
authors.lastname: Parsons
authors.forename: Dominic
authors.initials: D
authors.lastname: Ryan
authors.forename: Martin
authors.initials: M
authors.lastname: Fisher
authors.forename: David
authors.initials: D
authors.lastname: Williams
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Dales
authors.forename: Michael A
authors.initials: MA
authors.lastname: Patane
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pantoliano
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000085962:Angiotensin-Converting Enzyme 2; D001665:Binding Sites; D002268:Carboxypeptidases / Q000737:chemistry*; D002384:Catalysis; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D007703:Peptidyl-Dipeptidase A; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D000085064:Receptors, Coronavirus; D011991:Receptors, Virus / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D015032:Zinc / Q000737:chemistry
chemical_list: C486469:2-(1-carboxy-2-(3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl)ethylamino)-4-methylpentanoic acid; D000596:Amino Acids; D004791:Enzyme Inhibitors; D007093:Imidazoles; D000085064:Receptors, Coronavirus; D011991:Receptors, Virus; D002268:Carboxypeptidases; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2; D007930:Leucine; D015032:Zinc