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PDBsum entry 2wd3

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protein ligands metals links
Lyase PDB id
2wd3
Jmol
Contents
Protein chain
257 a.a. *
Ligands
MS4 ×2
Metals
_ZN
Waters ×290
* Residue conservation analysis
PDB id:
2wd3
Name: Lyase
Title: Highly potent first examples of dual aromatase-steroid sulfatase inhibitors based on a biphenyl template
Structure: Carbonic anhydrase 2. Chain: a. Fragment: residues 2-260. Synonym: carbonic anhydrase ii, carbonate dehydratase ii, carbonic anhydrasE C, ca-ii, cac. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Resolution:
1.80Å     R-factor:   0.153     R-free:   0.188
Authors: L.W.L.Woo,T.Jackson,A.Putey,G.Cozier,P.Leonard,K.R.Acharya, S.K.Chander,A.Purohit,M.J.Reed,B.V.L.Potter
Key ref: L.W.Woo et al. (2010). Highly potent first examples of dual aromatase-steroid sulfatase inhibitors based on a biphenyl template. J Med Chem, 53, 2155-2170. PubMed id: 20148564
Date:
19-Mar-09     Release date:   23-Feb-10    
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   9 terms 
  Biological process     angiotensin-mediated signaling pathway   20 terms 
  Biochemical function     protein binding     5 terms  

 

 
    Added reference    
 
 
J Med Chem 53:2155-2170 (2010)
PubMed id: 20148564  
 
 
Highly potent first examples of dual aromatase-steroid sulfatase inhibitors based on a biphenyl template.
L.W.Woo, T.Jackson, A.Putey, G.Cozier, P.Leonard, K.R.Acharya, S.K.Chander, A.Purohit, M.J.Reed, B.V.Potter.
 
  ABSTRACT  
 
Single agents against multiple drug targets are of increasing interest. Hormone-dependent breast cancer (HDBC) may be more effectively treated by dual inhibition of aromatase and steroid sulfatase (STS). The aromatase inhibitory pharmacophore was thus introduced into a known biphenyl STS inhibitor to give a series of novel dual aromatase-sulfatase inhibitors (DASIs). Several compounds are good aromatase or STS inhibitors and DASI 20 (IC(50): aromatase, 2.0 nM; STS, 35 nM) and its chlorinated congener 23 (IC(50): aromatase, 0.5 nM; STS, 5.5 nM) are examples that show exceptional dual potency in JEG-3 cells. Both biphenyls share a para-sulfamate-containing ring B and a ring A, which contains a triazol-1-ylmethyl meta to the biphenyl bridge and para to a nitrile. At 1 mg/kg po, 20 and 23 reduced plasma estradiol levels strongly and inhibited liver STS activity potently in vivo. 23 is nonestrogenic and potently inhibits carbonic anhydrase II (IC(50) 86 nM). A complex was crystallized and its structure was solved by X-ray crystallography. This class of DASI should encourage further development toward multitargeted therapeutic intervention in HDBC.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20632362 P.M.Wood, L.W.Woo, J.R.Labrosse, M.P.Thomas, M.F.Mahon, S.K.Chander, A.Purohit, M.J.Reed, and B.V.Potter (2010).
Bicyclic derivatives of the potent dual aromatase-steroid sulfatase inhibitor 2-bromo-4-{[(4-cyanophenyl)(4h-1,2,4-triazol-4-yl)amino]methyl}phenylsulfamate: synthesis, SAR, crystal structure, and in vitro and in vivo activities.
  ChemMedChem, 5, 1577-1593.  
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