PDBsum entry 3l3n

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Hydrolase PDB id
Protein chain
575 a.a. *
_CL ×2
Waters ×176
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Testis ace co-crystal structure with novel inhibitor lisw
Structure: Angiotensin-converting enzyme. Chain: a. Fragment: peptidase m2 2, residues 642-1232. Synonym: ace, dipeptidyl carboxypeptidase i, kininase ii, angiotensin-converting enzyme, soluble form. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ace, dcp, dcp1. Expressed in: cricetulus griseus. Expression_system_taxid: 10029.
2.30Å     R-factor:   0.226     R-free:   0.266
Authors: J.M.Watermeyer,W.L.Kroger,H.G.O'Neil,B.T.Sewell,E.D.Sturrock
Key ref: J.M.Watermeyer et al. (2010). Characterization of domain-selective inhibitor binding in angiotensin-converting enzyme using a novel derivative of lisinopril. Biochem J, 428, 67-74. PubMed id: 20233165
17-Dec-09     Release date:   28-Apr-10    
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
* 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  


Biochem J 428:67-74 (2010)
PubMed id: 20233165  
Characterization of domain-selective inhibitor binding in angiotensin-converting enzyme using a novel derivative of lisinopril.
J.M.Watermeyer, W.L.Kröger, H.G.O'Neill, B.T.Sewell, E.D.Sturrock.
Human ACE (angiotensin-converting enzyme) (EC is an important drug target because of its role in the regulation of blood pressure via the renin-angiotensin-aldosterone system. Somatic ACE comprises two homologous domains, the differing substrate preferences of which present a new avenue for domain-selective inhibitor design. We have co-crystallized lisW-S, a C-domain-selective derivative of the drug lisinopril, with human testis ACE and determined a structure using X-ray crystallography to a resolution of 2.30 A (1 A=0.1 nm). In this structure, lisW-S is seen to have a similar binding mode to its parent compound lisinopril, but the P2' tryptophan moiety takes a different conformation to that seen in other inhibitors having a tryptophan residue in this position. We have examined further the domain-specific interactions of this inhibitor by mutating C-domain-specific active-site residues to their N domain equivalents, then assessing the effect of the mutation on inhibition by lisW-S using a fluorescence-based assay. Kinetics analysis shows a 258-fold domain-selectivity that is largely due to the co-operative effect of C-domain-specific residues in the S2' subsite. The high affinity and selectivity of this inhibitor make it a good lead candidate for cardiovascular drug development.

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
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