PDBsum entry 1uze

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Metalloprotease PDB id
Protein chain
575 a.a. *
_CL ×2
Waters ×456
* Residue conservation analysis
PDB id:
Name: Metalloprotease
Title: Complex of the anti-hypertensive drug enalaprilat and the human testicular angiotensin i-converting enzyme
Structure: Angiotensin converting enzyme. Chain: a. Fragment: extracellular domain, residues 68-656. Synonym: ace-t, dipeptidyl carboxypeptidase i, kininase ii. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Organ: testis. Expressed in: chinese hamster ovary. Expression_system_cell_line: cho.
1.82Å     R-factor:   0.188     R-free:   0.211
Authors: R.Natesh,S.L.U.Schwager,H.R.Evans,E.D.Sturrock,K.R.Acharya
Key ref:
R.Natesh et al. (2004). Structural details on the binding of antihypertensive drugs captopril and enalaprilat to human testicular angiotensin I-converting enzyme. Biochemistry, 43, 8718-8724. PubMed id: 15236580 DOI: 10.1021/bi049480n
11-Mar-04     Release date:   16-Jul-04    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P12821  (ACE_HUMAN) -  Angiotensin-converting enzyme
1306 a.a.
575 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 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/bi049480n Biochemistry 43:8718-8724 (2004)
PubMed id: 15236580  
Structural details on the binding of antihypertensive drugs captopril and enalaprilat to human testicular angiotensin I-converting enzyme.
R.Natesh, S.L.Schwager, H.R.Evans, E.D.Sturrock, K.R.Acharya.
Angiotensin converting enzyme (ACE) plays a critical role in the circulating or endocrine renin-angiotensin system (RAS) as well as the local regulation that exists in tissues such as the myocardium and skeletal muscle. Here we report the high-resolution crystal structures of testis ACE (tACE) in complex with the first successfully designed ACE inhibitor captopril and enalaprilat, the Phe-Ala-Pro analogue. We have compared these structures with the recently reported structure of a tACE-lisinopril complex [Natesh et al. (2003) Nature 421, 551-554]. The analyses reveal that all three inhibitors make direct interactions with the catalytic Zn(2+) ion at the active site of the enzyme: the thiol group of captopril and the carboxylate group of enalaprilat and lisinopril. Subtle differences are also observed at other regions of the binding pocket. These are compared with N-domain models and discussed with reference to published biochemical data. The chloride coordination geometries of the three structures are discussed and compared with other ACE analogues. It is anticipated that the molecular details provided by these structures will be used to improve the binding and/or the design of new, more potent domain-specific inhibitors of ACE that could serve as new generation antihypertensive drugs.

Literature references that cite this PDB file's key reference

  PubMed id Reference
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
21328404 V.Hähnke, A.Klenner, F.Rippmann, and G.Schneider (2011).
Pharmacophore alignment search tool: Influence of the third dimension on text-based similarity searching.
  J Comput Chem, 32, 1618-1634.  
19908272 D.M.Krüger, and A.Evers (2010).
Comparison of structure- and ligand-based virtual screening protocols considering hit list complementarity and enrichment factors.
  ChemMedChem, 5, 148-158.  
20014331 G.A.Dalkas, D.Marchand, J.C.Galleyrand, J.Martinez, G.A.Spyroulias, P.Cordopatis, and F.Cavelier (2010).
Study of a lipophilic captopril analogue binding to angiotensin I converting enzyme.
  J Pept Sci, 16, 91-97.  
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
18816584 A.S.Pina, and A.C.Roque (2009).
Studies on the molecular recognition between bioactive peptides and angiotensin-converting enzyme.
  J Mol Recognit, 22, 162-168.  
19430822 N.K.Rao, A.Yadav, and S.Kumar Singh (2009).
An ab initio quantum mechanical drug designing procedure: application to the design of balanced dual ACE/NEP inhibitors.
  J Mol Model, 15, 1447-1462.  
19329331 S.T.Moe, A.B.Thompson, G.M.Smith, R.A.Fredenburg, R.L.Stein, and A.R.Jacobson (2009).
Botulinum neurotoxin serotype A inhibitors: small-molecule mercaptoacetamide analogs.
  Bioorg Med Chem, 17, 3072-3079.  
18563261 B.M.Liénard, G.Garau, L.Horsfall, A.I.Karsisiotis, C.Damblon, P.Lassaux, C.Papamicael, G.C.Roberts, M.Galleni, O.Dideberg, J.M.Frère, and C.J.Schofield (2008).
Structural basis for the broad-spectrum inhibition of metallo-beta-lactamases by thiols.
  Org Biomol Chem, 6, 2282-2294.
PDB codes: 2qds 2qdt
19021774 C.A.Rushworth, J.L.Guy, and A.J.Turner (2008).
Residues affecting the chloride regulation and substrate selectivity of the angiotensin-converting enzymes (ACE and ACE2) identified by site-directed mutagenesis.
  FEBS J, 275, 6033-6042.  
17261801 A.Medlock, L.Swartz, T.A.Dailey, H.A.Dailey, and W.N.Lanzilotta (2007).
Substrate interactions with human ferrochelatase.
  Proc Natl Acad Sci U S A, 104, 1789-1793.
PDB codes: 2hrc 2hre
17429823 B.M.McArdle, and R.J.Quinn (2007).
Identification of protein fold topology shared between different folds inhibited by natural products.
  Chembiochem, 8, 788-798.  
17654623 F.Tian, P.Zhou, F.Lv, R.Song, and Z.Li (2007).
Three-dimensional holograph vector of atomic interaction field (3D-HoVAIF): a novel rotation-translation invariant 3D structure descriptor and its applications to peptides.
  J Pept Sci, 13, 549-566.  
16972307 S.S.Vamvakas, L.Leondiadis, G.Pairas, E.Manessi-Zoupa, G.A.Spyroulias, and P.Cordopatis (2007).
Expression, purification, and physicochemical characterization of the N-terminal active site of human angiotensin-I converting enzyme.
  J Pept Sci, 13, 31-36.  
17135201 Y.Wang, K.J.Addess, J.Chen, L.Y.Geer, J.He, S.He, S.Lu, T.Madej, A.Marchler-Bauer, P.A.Thiessen, N.Zhang, and S.H.Bryant (2007).
MMDB: annotating protein sequences with Entrez's 3D-structure database.
  Nucleic Acids Res, 35, D298-D300.  
17042482 J.M.Watermeyer, B.T.Sewell, S.L.Schwager, R.Natesh, H.R.Corradi, K.R.Acharya, and E.D.Sturrock (2006).
Structure of testis ACE glycosylation mutants and evidence for conserved domain movement.
  Biochemistry, 45, 12654-12663.
PDB codes: 2iul 2iux
16606345 P.Redelinghuys, A.T.Nchinda, K.Chibale, and E.D.Sturrock (2006).
Novel ketomethylene inhibitors of angiotensin I-converting enzyme (ACE): inhibition and molecular modelling.
  Biol Chem, 387, 461-466.  
16784456 R.Bohacek, M.S.Boosalis, C.McMartin, D.V.Faller, and S.P.Perrine (2006).
Identification of novel small-molecule inducers of fetal hemoglobin using pharmacophore and 'PSEUDO' receptor models.
  Chem Biol Drug Des, 67, 318-328.  
16403023 R.J.Bingham, V.Dive, S.E.Phillips, A.D.Shirras, and R.E.Isaac (2006).
Structural diversity of angiotensin-converting enzyme.
  FEBS J, 273, 362-373.  
15883972 A.G.Tzakos, and I.P.Gerothanassis (2005).
Domain-selective ligand-binding modes and atomic level pharmacophore refinement in angiotensin I converting enzyme (ACE) inhibitors.
  Chembiochem, 6, 1089-1103.  
16307311 D.J.Kuster, and G.R.Marshall (2005).
Validated ligand mapping of ACE active site.
  J Comput Aided Mol Des, 19, 609-615.  
16008552 J.L.Guy, R.M.Jackson, H.A.Jensen, N.M.Hooper, and A.J.Turner (2005).
Identification of critical active-site residues in angiotensin-converting enzyme-2 (ACE2) by site-directed mutagenesis.
  FEBS J, 272, 3512-3520.  
16271036 N.A.Moiseeva, P.V.Binevski, I.I.Baskin, V.A.Palyulin, and O.A.Kost (2005).
Role of two chloride-binding sites in functioning of testicular angiotensin-converting enzyme.
  Biochemistry (Mosc), 70, 1167-1172.  
15615692 N.Naqvi, K.Liu, R.M.Graham, and A.Husain (2005).
Molecular basis of exopeptidase activity in the C-terminal domain of human angiotensin I-converting enzyme: insights into the origins of its exopeptidase activity.
  J Biol Chem, 280, 6669-6675.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.