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PDBsum entry 4mo8

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protein ligands metals links
Lyase/lyase inhibitor PDB id
4mo8
Jmol PyMol
Contents
Protein chain
257 a.a.
Ligands
2VQ
Metals
_ZN
Waters ×199
PDB id:
4mo8
Name: Lyase/lyase inhibitor
Title: The crystal structure of the human carbonic anhydrase ii in with n-[2-(2-methyl-5-nitro-1h-imidazol-1-yl)ethyl]sulfamid
Structure: Carbonic anhydrase 2. Chain: a. Synonym: carbonate dehydratase ii, carbonic anhydrasE C, ca carbonic anhydrase ii, ca-ii. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ca2. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
1.85Å     R-factor:   0.163     R-free:   0.196
Authors: V.Alterio,G.De Simone
Key ref: M.Rami et al. (2013). Hypoxia-targeting carbonic anhydrase IX inhibitors by a new series of nitroimidazole-sulfonamides/sulfamides/sulfamates. J Med Chem, 56, 8512-8520. PubMed id: 24128000 DOI: 10.1021/jm4009532
Date:
11-Sep-13     Release date:   30-Oct-13    
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  - Carbonic anhydrase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: H2CO3 = CO2 + H2O
H(2)CO(3)
= CO(2)
+ H(2)O
      Cofactor: Zn(2+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular space   11 terms 
  Biological process     angiotensin-mediated signaling pathway   22 terms 
  Biochemical function     protein binding     6 terms  

 

 
    Added reference    
 
 
DOI no: 10.1021/jm4009532 J Med Chem 56:8512-8520 (2013)
PubMed id: 24128000  
 
 
Hypoxia-targeting carbonic anhydrase IX inhibitors by a new series of nitroimidazole-sulfonamides/sulfamides/sulfamates.
M.Rami, L.Dubois, N.K.Parvathaneni, V.Alterio, S.J.van Kuijk, S.M.Monti, P.Lambin, G.De Simone, C.T.Supuran, J.Y.Winum.
 
  ABSTRACT  
 
A series of nitroimidazoles incorporating sulfonamide/sulfamide/sulfamate moieties were designed and synthesized as radio/chemosensitizing agent targeting the tumor-associated carbonic anhydrase (CA) isoforms IX and XII. Most of the new compounds were nanomolar inhibitors of these isoforms. Crystallographic studies on the complex of hCA II with the lead sulfamide derivative of this series clarified the binding mode of this type of inhibitors in the enzyme active site cavity. Some of the best nitroimidazole CA IX inhibitors showed significant activity in vitro by reducing hypoxia-induced extracellular acidosis in HT-29 and HeLa cell lines. In vivo testing of the lead molecule in the sulfamide series, in cotreatment with doxorubicin, demonstrated a chemosensitization of CA IX containing tumors. Such CA inhibitors, specifically targeting the tumor-associated isoforms, are candidates for novel treatment strategies against hypoxic tumors overexpressing extracellular CA isozymes.
 

 

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