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PDBsum entry 3daz

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protein ligands metals links
Lyase PDB id
3daz
Jmol
Contents
Protein chain
257 a.a. *
Ligands
MZM
Metals
_ZN
Waters ×182
* Residue conservation analysis
PDB id:
3daz
Name: Lyase
Title: Use of carbonic anhydrase ii, ix active-site mimic, for the purpose of screening inhibitors for possible anti-cancer properties
Structure: Carbonic anhydrase 2. Chain: a. Synonym: carbonic anhydrase ii, carbonate dehydratase ii, ca-ii, carbonic anhydrasE C, cac. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ca2. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.60Å     R-factor:   0.163     R-free:   0.190
Authors: C.Genis,K.H.Sippel,N.Case,L.Govindasamy,M.Agbandje-Mckenna, R.Mckenna
Key ref: C.Genis et al. (2009). Design of a carbonic anhydrase IX active-site mimic to screen inhibitors for possible anticancer properties. Biochemistry, 48, 1322-1331. PubMed id: 19170619
Date:
30-May-08     Release date:   03-Mar-09    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00918  (CAH2_HUMAN) -  Carbonic anhydrase 2
Seq:
Struc:
260 a.a.
257 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.4.2.1.1  - Carbonate dehydratase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: H2CO3 = CO2 + H2O
H(2)CO(3)
= CO(2)
+ H(2)O
      Cofactor: Zinc
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular space   10 terms 
  Biological process     angiotensin-mediated signaling pathway   20 terms 
  Biochemical function     protein binding     5 terms  

 

 
    Added reference    
 
 
Biochemistry 48:1322-1331 (2009)
PubMed id: 19170619  
 
 
Design of a carbonic anhydrase IX active-site mimic to screen inhibitors for possible anticancer properties.
C.Genis, K.H.Sippel, N.Case, W.Cao, B.S.Avvaru, L.J.Tartaglia, L.Govindasamy, C.Tu, M.Agbandje-McKenna, D.N.Silverman, C.J.Rosser, R.McKenna.
 
  ABSTRACT  
 
Recently, a convincing body of evidence has accumulated suggesting that the overexpression of carbonic anhydrase isozyme IX (CA IX) in some cancers contributes to the acidification of the extracellular matrix, which in turn promotes the growth and metastasis of the tumor. These observations have made CA IX an attractive drug target for the selective treatment of certain cancers. Currently, there is no available X-ray crystal structure of CA IX, and this lack of availability has hampered the rational design of selective CA IX inhibitors. In light of these observations and on the basis of structural alignment homology, using the crystal structure of carbonic anhydrase II (CA II) and the sequence of CA IX, a double mutant of CA II with Ala65 replaced by Ser and Asn67 replaced by Gln has been constructed to resemble the active site of CA IX. This CA IX mimic has been characterized kinetically using (18)O-exchange and structurally using X-ray crystallography, alone and in complex with five CA sulfonamide-based inhibitors (acetazolamide, benzolamide, chlorzolamide, ethoxzolamide, and methazolamide), and compared to CA II. This structural information has been evaluated by both inhibition studies and in vitro cytotoxicity assays and shows a correlated structure-activity relationship. Kinetic and structural studies of CA II and CA IX mimic reveal chlorzolamide to be a more potent inhibitor of CA IX, inducing an active-site conformational change upon binding. Additionally, chlorzolamide appears to be cytotoxic to prostate cancer cells. This preliminary study demonstrates that the CA IX mimic may provide a useful model to design more isozyme-specific CA IX inhibitors, which may lead to development of new therapeutic treatments of some cancers.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21244635 A.Stander, F.Joubert, and A.Joubert (2011).
Docking, synthesis, and in vitro evaluation of antimitotic estrone analogs.
  Chem Biol Drug Des, 77, 173-181.  
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