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PDBsum entry 3ml2

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protein ligands metals links
Lyase/lyase inhibitor PDB id
3ml2
Jmol
Contents
Protein chain
257 a.a.
Ligands
SU0
GOL
Metals
_ZN
Waters ×185
PDB id:
3ml2
Name: Lyase/lyase inhibitor
Title: Human carbonic anhydsase ii in complex with an aryl sulfonam inhibitor
Structure: Carbonic anhydrase 2. Chain: a. Synonym: carbonic anhydrase ii, ca-ii, carbonate dehydratas carbonic anhydrasE C, cac. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ca2, hca2. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Resolution:
1.80Å     R-factor:   0.189     R-free:   0.222
Authors: B.S.Avvaru,J.Wagner,A.H.Robbins,R.Mckenna
Key ref: J.Wagner et al. (2010). Coumarinyl-substituted sulfonamides strongly inhibit several human carbonic anhydrase isoforms: solution and crystallographic investigations. Bioorg Med Chem, 18, 4873-4878. PubMed id: 20598552 DOI: 10.1016/j.bmc.2010.06.028
Date:
16-Apr-10     Release date:   20-Apr-11    
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: 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   21 terms 
  Biochemical function     protein binding     5 terms  

 

 
    Added reference    
 
 
DOI no: 10.1016/j.bmc.2010.06.028 Bioorg Med Chem 18:4873-4878 (2010)
PubMed id: 20598552  
 
 
Coumarinyl-substituted sulfonamides strongly inhibit several human carbonic anhydrase isoforms: solution and crystallographic investigations.
J.Wagner, B.S.Avvaru, A.H.Robbins, A.Scozzafava, C.T.Supuran, R.McKenna.
 
  ABSTRACT  
 
We investigated a series of coumarinyl-substituted aromatic sulfonamides as inhibitors of four carbonic anhydrase (CA, EC 4.2.1.1) isoforms with medical applications, the cytosolic hCA I, and II, and the transmembrane, tumor-associated hCA IX and XII. Compounds incorporating 7-methoxy-coumarin-4-yl-acetamide-tails and benzenesulfonamide and benzene-1,3-disulfonamide scaffolds showed medium potency inhibition of hCA I (K(I)s of 73-131nM), effective hCA II inhibition (K(I)s of 9.1-36nM) and less effective hCA IX and XII inhibition (K(I)s of 55-128nM). Only one compound, the derivatized 4-amino-6-trifluoromethyl-benzene-1,3-disulfonamide with the coumarinyl tail, showed effective inhibition of the transmembrane isoforms, with K(I)s of 5.9-14.2nM, although it was less effective as hCA I and II inhibitor (K(I)s of 36-120nM). An X-ray crystal structure of hCA II in complex with 4-(7-methoxy-coumarin-4-yl-acetamido)-benzenesulfonamide (K(I) of 9.1nM against hCA II) showed the intact inhibitor coordinated to the zinc ion from the enzyme active site by the sulfonamide moiety, and participating in a edge-to-face stacking with Phe131, in addition to other hydrophobic and hydrophilic interactions with water molecules and amino acid residues from the active site. Thus, sulfonamides incorporating coumarin rings have a distinct inhibition mechanism compared to the coumarins, and may lead to compounds with interesting inhibition profiles against various alpha-CAs found in mammals or parasites, such as Plasmodium falciparum.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21515057 F.Carta, V.Garaj, A.Maresca, J.Wagner, B.S.Avvaru, A.H.Robbins, A.Scozzafava, R.McKenna, and C.T.Supuran (2011).
Sulfonamides incorporating 1,3,5-triazine moieties selectively and potently inhibit carbonic anhydrase transmembrane isoforms IX, XII and XIV over cytosolic isoforms I and II: Solution and X-ray crystallographic studies.
  Bioorg Med Chem, 19, 3105-3119.
PDB codes: 3mmf 3mna
21549597 F.Mincione, F.Benedini, S.Biondi, A.Cecchi, C.Temperini, G.Formicola, I.Pacileo, A.Scozzafava, E.Masini, and C.T.Supuran (2011).
Synthesis and crystallographic analysis of new sulfonamides incorporating NO-donating moieties with potent antiglaucoma action.
  Bioorg Med Chem Lett, 21, 3216-3221.
PDB code: 3ni5
20922253 F.Pacchiano, M.Aggarwal, B.S.Avvaru, A.H.Robbins, A.Scozzafava, R.McKenna, and C.T.Supuran (2010).
Selective hydrophobic pocket binding observed within the carbonic anhydrase II active site accommodate different 4-substituted-ureido-benzenesulfonamides and correlate to inhibitor potency.
  Chem Commun (Camb), 46, 8371-8373.
PDB codes: 3mzc 3n0n 3n2p 3n3j 3n4b
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