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PDBsum entry 4kp8

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protein ligands metals Protein-protein interface(s) links
Lyase/lyase inhibitor PDB id
4kp8
Jmol
Contents
Protein chains
261 a.a.
Ligands
E1G ×3
DMS
PEG ×2
EDO
Metals
_ZN ×4
Waters ×997
PDB id:
4kp8
Name: Lyase/lyase inhibitor
Title: Crystal structure of catalytic domain of human carbonic anhy isozyme xii with 3-[(pyrimidin-2-ylsulfanyl)acetyl]benzenes
Structure: Carbonic anhydrase 12. Chain: a, b, c, d. Fragment: catalytic domain, unp residues 30-291. Synonym: carbonate dehydratase xii, carbonic anhydrase xii, tumor antigen hom-rcc-3.1.3. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ca12. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.80Å     R-factor:   0.204     R-free:   0.251
Authors: A.Smirnov,E.Manakova,S.Grazulis
Key ref: E.Čapkauskaitė et al. (2013). Benzenesulfonamides with pyrimidine moiety as inhibitors of human carbonic anhydrases I, II, VI, VII, XII, and XIII. Bioorg Med Chem, 21, 6937-6947. PubMed id: 24103428 DOI: 10.1016/j.bmc.2013.09.029
Date:
13-May-13     Release date:   06-Nov-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
O43570  (CAH12_HUMAN) -  Carbonic anhydrase 12
Seq:
Struc:
354 a.a.
261 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)
Bound ligand (Het Group name = EDO)
matches with 40.00% similarity
+ 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     integral to membrane   1 term 
  Biological process     one-carbon metabolic process   1 term 
  Biochemical function     carbonate dehydratase activity     2 terms  

 

 
    Added reference    
 
 
DOI no: 10.1016/j.bmc.2013.09.029 Bioorg Med Chem 21:6937-6947 (2013)
PubMed id: 24103428  
 
 
Benzenesulfonamides with pyrimidine moiety as inhibitors of human carbonic anhydrases I, II, VI, VII, XII, and XIII.
E.Čapkauskaitė, A.Zubrienė, A.Smirnov, J.Torresan, M.Kišonaitė, J.Kazokaitė, J.Gylytė, V.Michailovienė, V.Jogaitė, E.Manakova, S.Gražulis, S.Tumkevičius, D.Matulis.
 
  ABSTRACT  
 
Two groups of benzenesulfonamide derivatives, bearing pyrimidine moieties, were designed and synthesized as inhibitors of carbonic anhydrases (CA). Their binding affinities to six recombinant human CA isoforms I, II, VI, VII, XII, and XIII were determined by the thermal shift assay (TSA). The binding of several inhibitors was measured by isothermal titration calorimetry (ITC). Direct demonstration of compound inhibition was achieved by determining the inhibition constant by stopped-flow CO2 hydration assay. The most potent compounds demonstrated selectivity towards isoform I and affinities of 0.5nM. The crystal structures of selected compounds in complex with CA II, XII, and XIII were determined to atomic resolution. Compounds described here were compared with previously published pyrimidinebenzenesulfonamides.(1) Systematic structure-activity analysis of 40 compound interactions with six isoforms yields clues for the design of compounds with greater affinities and selectivities towards target CA isoforms.