PDBsum entry 3bkl

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Hydrolase PDB id
Protein chain
582 a.a. *
NAG ×2
ACT ×3
_CL ×2
Waters ×233
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Testis ace co-crystal structure with ketone ace inhibitor ka
Structure: Angiotensin-converting enzyme, somatic isoform. Chain: a. Fragment: peptidase m2 2 domain. Synonym: dipeptidyl carboxypeptidase i,kininase ii,cd143 an engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ace, dcp, dcp1. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: cho-k1.
2.18Å     R-factor:   0.200     R-free:   0.240
Authors: J.M.Watermeyer,W.L.Kroger,H.G.O'Neill,B.T.Sewell,E.D.Sturroc
Key ref: J.M.Watermeyer et al. (2008). Probing the basis of domain-dependent inhibition using novel ketone inhibitors of Angiotensin-converting enzyme. Biochemistry, 47, 5942-5950. PubMed id: 18457420 DOI: 10.1021/bi8002605
07-Dec-07     Release date:   10-Jun-08    
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Protein chain
Pfam   ArchSchema ?
P12821  (ACE_HUMAN) -  Angiotensin-converting enzyme
1306 a.a.
582 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 5 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.  - Peptidyl-dipeptidase A.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Release of a C-terminal dipeptide, oligopeptide-|-Xaa-Xbb, when Xaa is not Pro, and Xbb is neither Asp nor Glu. Converts angiotensin I to angiotensin II.
      Cofactor: Zn(2+)
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   1 term 
  Biological process     proteolysis   1 term 
  Biochemical function     metallopeptidase activity     2 terms  


DOI no: 10.1021/bi8002605 Biochemistry 47:5942-5950 (2008)
PubMed id: 18457420  
Probing the basis of domain-dependent inhibition using novel ketone inhibitors of Angiotensin-converting enzyme.
J.M.Watermeyer, W.L.Kröger, H.G.O'Neill, B.T.Sewell, E.D.Sturrock.
Human angiotensin-converting enzyme (ACE) has two homologous domains, the N and C domains, with differing substrate preferences. X-ray crystal structures of the C and N domains complexed with various inhibitors have allowed identification of active site residues that might be important for the molecular basis of this selectivity. However, it is unclear to what extent the different residues contribute to substrate domain selectivity. Here, cocrystal structures of human testis ACE, equivalent to the C domain, have been determined with two novel C domain-selective ketomethylene inhibitors, (5 S)-5-[( N-benzoyl)amino]-4-oxo-6-phenylhexanoyl- l-tryptophan (kAW) and (5 S)-5-[( N-benzoyl)amino]-4-oxo-6-phenylhexanoyl- l-phenylalanine (kAF). The ketone groups of both inhibitors bind to the zinc ion as a hydrated geminal diolate, demonstrating the ability of the active site to catalyze the formation of the transition state. Moreover, active site residues involved in inhibitor binding have been mutated to their N domain counterparts, and the effect of the mutations on inhibitor binding has been determined. The C domain selectivity of these inhibitors was found to result from interactions between bulky hydrophobic side chain moieties and C domain-specific residues F391, V518, E376, and V380 (numbering of testis ACE). Mutation of these residues decreased the affinity for the inhibitors 4-20-fold. T282, V379, E403, D453, and S516 did not contribute individually to C domain-selective inhibitor binding. Further domain-selective inhibitor design should focus on increasing both the affinity and selectivity of the side chain moieties.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21130035 K.E.Bernstein, X.Z.Shen, R.A.Gonzalez-Villalobos, S.Billet, D.Okwan-Duodu, F.S.Ong, and S.Fuchs (2011).
Different in vivo functions of the two catalytic domains of angiotensin-converting enzyme (ACE).
  Curr Opin Pharmacol, 11, 105-111.  
21352096 M.Akif, S.L.Schwager, C.S.Anthony, B.Czarny, F.Beau, V.Dive, E.D.Sturrock, and K.R.Acharya (2011).
Novel mechanism of inhibition of human angiotensin-I-converting enzyme (ACE) by a highly specific phosphinic tripeptide.
  Biochem J, 436, 53-59.
PDB codes: 2xy9 2xyd
20233165 J.M.Watermeyer, W.L.Kröger, H.G.O'Neill, B.T.Sewell, and E.D.Sturrock (2010).
Characterization of domain-selective inhibitor binding in angiotensin-converting enzyme using a novel derivative of lisinopril.
  Biochem J, 428, 67-74.
PDB code: 3l3n
20454656 S.M.Danilov, S.Kalinin, Z.Chen, E.I.Vinokour, A.B.Nesterovitch, D.E.Schwartz, O.Gribouval, M.C.Gubler, and R.D.Minshall (2010).
Angiotensin I-converting enzyme Gln1069Arg mutation impairs trafficking to the cell surface resulting in selective denaturation of the C-domain.
  PLoS One, 5, e10438.  
19558329 C.E.Cunha, H.d.e. .F.Magliarelli, T.Paschoalin, A.T.Nchinda, J.C.Lima, M.A.Juliano, P.B.Paiva, E.D.Sturrock, L.R.Travassos, and A.K.Carmona (2009).
Catalytic properties of recombinant dipeptidyl carboxypeptidase from Escherichia coli: a comparative study with angiotensin I-converting enzyme.
  Biol Chem, 390, 931-940.  
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