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PDBsum entry 2c6f

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protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
2c6f
Jmol
Contents
Protein chain
612 a.a. *
Ligands
NAG ×9
NAG-NAG ×2
ACT ×3
GOL ×2
Metals
_ZN ×2
_CL ×2
Waters ×24
* Residue conservation analysis
PDB id:
2c6f
Name: Hydrolase
Title: Structure of human somatic angiontensin-i converting enzyme n domain
Structure: Angiotensin-converting enzyme, somatic isoform. Chain: a, b. Fragment: n domain, residues 30-641. Synonym: somatic angiotensin-i converting enzyme n domain, dipeptidyl carboxypeptidase i, kininase ii, cd143 antigen. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: cho-k1.
Resolution:
3.01Å     R-factor:   0.224     R-free:   0.273
Authors: H.R.Corradi,S.L.U.Schwager,A.Nichinda,E.D.Sturrock, K.R.Acharya
Key ref:
H.R.Corradi et al. (2006). Crystal Structure of the N Domain of Human Somatic Angiotensin I-converting Enzyme Provides a Structural Basis for Domain-specific Inhibitor Design. J Mol Biol, 357, 964-974. PubMed id: 16476442 DOI: 10.1016/j.jmb.2006.01.048
Date:
09-Nov-05     Release date:   08-Nov-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P12821  (ACE_HUMAN) -  Angiotensin-converting enzyme
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1306 a.a.
612 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.4.15.1  - 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: 10.1016/j.jmb.2006.01.048 J Mol Biol 357:964-974 (2006)
PubMed id: 16476442  
 
 
Crystal Structure of the N Domain of Human Somatic Angiotensin I-converting Enzyme Provides a Structural Basis for Domain-specific Inhibitor Design.
H.R.Corradi, S.L.Schwager, A.T.Nchinda, E.D.Sturrock, K.R.Acharya.
 
  ABSTRACT  
 
Human somatic angiotensin I-converting enzyme (sACE) is a key regulator of blood pressure and an important drug target for combating cardiovascular and renal disease. sACE comprises two homologous metallopeptidase domains, N and C, joined by an inter-domain linker. Both domains are capable of cleaving the two hemoregulatory peptides angiotensin I and bradykinin, but differ in their affinities for a range of other substrates and inhibitors. Previously we determined the structure of testis ACE (C domain); here we present the crystal structure of the N domain of sACE (both in the presence and absence of the antihypertensive drug lisinopril) in order to aid the understanding of how these two domains differ in specificity and function. In addition, the structure of most of the inter-domain linker allows us to propose relative domain positions for sACE that may contribute to the domain cooperativity. The structure now provides a platform for the design of "domain-specific" second-generation ACE inhibitors.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. Sequence alignment of the sACE N domain with tACE and ACE2. Helices are highlighted in yellow and strands in blue. The linker region is shown in pink. Helices are numbered sequentially whether a or 3[10], and 3[10] helices are shown with red letters. Chloride I coordinating residues are boxed in dark blue, chloride II in black, and the zinc binding motif in red.
Figure 3.
Figure 3. (a) Close up of the active site of the N domain (blue/green) and tACE (pink) with the zinc ion in green and the conserved chloride ion in red. Lisinopril is shown in grey/pink for the N domain/tACE, respectively. The lisinopril binding residues are shown in ball and stick. Residues common between the N domain and tACE are in grey (N domain numbering) with differing residues for these two proteins shown in blue/green and pink, respectively. (b) A different orientation of the native N domain active site (blue/green) with RXP407 (grey) approximately positioned using molecular docking. Residues differing between the N domain and tACE (equivalent to the C domain) in the S[2'] and S[2] subsites and the chloride coordinating residues are shown in ball and stick. Residues conserved between the N domain and tACE are shown in grey (N domain numbering), N domain residues are shown in blue/green and tACE residues in pink. The chloride ion is shown in red.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2006, 357, 964-974) copyright 2006.  
  Figures were selected by an automated process.  

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
20826823 C.S.Anthony, H.R.Corradi, S.L.Schwager, P.Redelinghuys, D.Georgiadis, V.Dive, K.R.Acharya, and E.D.Sturrock (2010).
The N domain of human angiotensin-I-converting enzyme: the role of N-glycosylation and the crystal structure in complex with an N domain-specific phosphinic inhibitor, RXP407.
  J Biol Chem, 285, 35685-35693.
PDB codes: 2oc2 3nxq
20065150 E.G.Erdös, F.Tan, and R.A.Skidgel (2010).
Angiotensin I-converting enzyme inhibitors are allosteric enhancers of kinin B1 and B2 receptor function.
  Hypertension, 55, 214-220.  
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
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.  
20634989 Z.Spyranti, A.S.Galanis, G.Pairas, G.A.Spyroulias, E.Manessi-Zoupa, and P.Cordopatis (2010).
Synthetic peptides as structural maquettes of Angiotensin-I converting enzyme catalytic sites.
  Bioinorg Chem Appl, (), 820476.  
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.  
19551715 S.S.Vamvakas, L.Leondiadis, G.Pairas, E.Manessi-Zoupa, G.A.Spyroulias, and P.Cordopatis (2009).
Folding in solution of the C-catalytic protein fragment of angiotensin-converting enzyme.
  J Pept Sci, 15, 504-510.  
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.  
18713002 H.G.O'Neill, P.Redelinghuys, S.L.Schwager, and E.D.Sturrock (2008).
The role of glycosylation and domain interactions in the thermal stability of human angiotensin-converting enzyme.
  Biol Chem, 389, 1153-1161.  
18672685 I.A.Naperova, I.V.Baliasnikova, M.N.Petrov, A.V.Vakhitova, V.V.Evdokimov, S.M.Danilov, and O.A.Kost (2008).
[Characteristics of monoclonal antibody binding with the C domain of human angiotensin converting enzyme]
  Bioorg Khim, 34, 358-364.  
17597519 M.Rella, J.L.Elliot, T.J.Revett, J.Lanfear, A.Phelan, R.M.Jackson, A.J.Turner, and N.M.Hooper (2007).
Identification and characterisation of the angiotensin converting enzyme-3 (ACE3) gene: a novel mammalian homologue of ACE.
  BMC Genomics, 8, 194.  
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
17044798 M.R.Ehlers (2006).
Safety issues associated with the use of angiotensin-converting enzyme inhibitors.
  Expert Opin Drug Saf, 5, 739-740.  
16895474 Z.L.Woodman, S.L.Schwager, P.Redelinghuys, A.J.Chubb, E.L.van der Merwe, M.R.Ehlers, and E.D.Sturrock (2006).
Homologous substitution of ACE C-domain regions with N-domain sequences: effect on processing, shedding, and catalytic properties.
  Biol Chem, 387, 1043-1051.  
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.