spacer
spacer

PDBsum entry 2f14

Go to PDB code: 
protein ligands metals links
Lyase PDB id
2f14
Jmol
Contents
Protein chain
257 a.a. *
Ligands
HGB
FL1
GOL ×2
Metals
_ZN
Waters ×299
* Residue conservation analysis
PDB id:
2f14
Name: Lyase
Title: Tne crystal structure of the human carbonic anhydrase ii in with a fluorescent inhibitor
Structure: Carbonic anhydrase 2. Chain: a. Synonym: carbonic anhydrase ii, carbonate dehydratase ii, c carbonic anhydrasE C. Ec: 4.2.1.1
Source: Homo sapiens. Human. Organism_taxid: 9606. Other_details: erythrocytes
Resolution:
1.71Å     R-factor:   0.172     R-free:   0.202
Authors: V.Alterio,C.Pedone,G.De Simone
Key ref: V.Alterio et al. (2006). Carbonic anhydrase inhibitors: X-ray and molecular modeling study for the interaction of a fluorescent antitumor sulfonamide with isozyme II and IX. J Am Chem Soc, 128, 8329-8335. PubMed id: 16787097 DOI: 10.1021/ja061574s
Date:
14-Nov-05     Release date:   24-Oct-06    
PROCHECK
Go to PROCHECK summary
 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    
 
 
DOI no: 10.1021/ja061574s J Am Chem Soc 128:8329-8335 (2006)
PubMed id: 16787097  
 
 
Carbonic anhydrase inhibitors: X-ray and molecular modeling study for the interaction of a fluorescent antitumor sulfonamide with isozyme II and IX.
V.Alterio, R.M.Vitale, S.M.Monti, C.Pedone, A.Scozzafava, A.Cecchi, G.De Simone, C.T.Supuran.
 
  ABSTRACT  
 
The X-ray crystal structure of the fluorescent antitumor sulfonamide carbonic anhydrase (CA, EC, 4.2.1.1) inhibitor (4-sulfamoylphenylethyl)thioureido fluorescein (1) in complex with the cytosolic isoform hCA II is reported, together with a modeling study of the adduct of 1 with the tumor-associated isoform hCA IX. Its binding to hCA II is similar to that of other benzesulfonamides, with the ionized sulfonamide coordinated to the Zn2+ ion within the enzyme active site, and also participating in a network of hydrogen bonds with residues Thr199 and Glu106. The scaffold of 1 did not establish polar interactions within the enzyme active site but made hydrophobic contacts (<4.5 A) with Gln92, Val121, Phe131, Val135, Leu198, Thr199, Thr200, and Pro202. The substituted 3-carboxy-amino-phenyl functionality was at van der Waals distance from Phe131, Gly132, and Val135. The bulky tricyclic fluorescein moiety was located at the rim of the active site, on the protein surface, and strongly interacted with the alpha-helix formed by residues Asp130-Val135. All these interactions were preserved in the hCA IX-1 adduct, but the carbonyl moiety of the fluorescein tail of 1 participates in a strong hydrogen bond with the guanidine moiety of Arg130, an amino acid characteristic of the hCA IX active site. This may account for the roughly 2 times higher affinity of 1 for hCA IX over hCA II and may explain why in vivo the compound specifically accumulates only in hypoxic tumors overexpressing CA IX and not in the normal tissues. The compound is in clinical studies as an imaging tool for acute hypoxic tumors.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21921921 D.Neri, and C.T.Supuran (2011).
Interfering with pH regulation in tumours as a therapeutic strategy.
  Nat Rev Drug Discov, 10, 767-777.  
19390153 R.Caliandro, B.Carrozzini, G.L.Cascarano, C.Giacovazzo, A.M.Mazzone, and D.Siliqi (2009).
EDM-DEDM and protein crystal structure solution.
  Acta Crystallogr D Biol Crystallogr, 65, 477-484.  
18167490 C.T.Supuran (2008).
Carbonic anhydrases: novel therapeutic applications for inhibitors and activators.
  Nat Rev Drug Discov, 7, 168-181.  
18430122 C.T.Supuran (2008).
Development of small molecule carbonic anhydrase IX inhibitors.
  BJU Int, 101, 39-40.  
18600270 C.Temperini, A.Cecchi, A.Scozzafava, and C.T.Supuran (2008).
Carbonic anhydrase inhibitors. Sulfonamide diuretics revisited--old leads for new applications?
  Org Biomol Chem, 6, 2499-2506.  
17880011 J.Y.Winum, M.Rami, A.Scozzafava, J.L.Montero, and C.Supuran (2008).
Carbonic anhydrase IX: a new druggable target for the design of antitumor agents.
  Med Res Rev, 28, 445-463.  
17661033 V.Hofmeister, D.Schrama, and J.C.Becker (2008).
Anti-cancer therapies targeting the tumor stroma.
  Cancer Immunol Immunother, 57, 1.  
18041760 V.Král, P.Mader, R.Collard, M.Fábry, M.Horejsí, P.Rezácová, M.Kozísek, J.Závada, J.Sedlácek, L.Rulísek, and J.Brynda (2008).
Stabilization of antibody structure upon association to a human carbonic anhydrase IX epitope studied by X-ray crystallography, microcalorimetry, and molecular dynamics simulations.
  Proteins, 71, 1275-1287.
PDB codes: 2hkf 2hkh
18335973 V.M.Krishnamurthy, G.K.Kaufman, A.R.Urbach, I.Gitlin, K.L.Gudiksen, D.B.Weibel, and G.M.Whitesides (2008).
Carbonic anhydrase as a model for biophysical and physical-organic studies of proteins and protein-ligand binding.
  Chem Rev, 108, 946.  
16996620 A.Thiry, J.M.Dogné, B.Masereel, and C.T.Supuran (2006).
Targeting tumor-associated carbonic anhydrase IX in cancer therapy.
  Trends Pharmacol Sci, 27, 566-573.  
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.