PDBsum entry 1i8z

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Lyase PDB id
Protein chain
258 a.a. *
Waters ×180
* Residue conservation analysis
PDB id:
Name: Lyase
Title: Carbonic anhydrase ii complexed with al-6629 2h-thieno[3,2- e]-1,2-thiazine-6-sulfonamide, 2-(3-methoxyphenyl)-3-(4- morpholinyl)-, 1,1-dioxide
Structure: Carbonic anhydrase ii. Chain: a. Synonym: carbonate dehydratase ii. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
1.93Å     R-factor:   0.223     R-free:   0.293
Authors: C.-Y.Kim,J.S.Chang,J.Liao,J.A.May,D.W.Christianson
Key ref: C.Y.Kim et al. (2002). Structural aspects of isozyme selectivity in the binding of inhibitors to carbonic anhydrases II and IV. J Med Chem, 45, 888-893. PubMed id: 11831900 DOI: 10.1021/jm010163d
16-Mar-01     Release date:   28-Mar-01    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P00918  (CAH2_HUMAN) -  Carbonic anhydrase 2
260 a.a.
258 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Carbonate dehydratase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: H2CO3 = CO2 + H2O
= 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: 10.1021/jm010163d J Med Chem 45:888-893 (2002)
PubMed id: 11831900  
Structural aspects of isozyme selectivity in the binding of inhibitors to carbonic anhydrases II and IV.
C.Y.Kim, D.A.Whittington, J.S.Chang, J.Liao, J.A.May, D.W.Christianson.
Carbonic anhydrase inhibitors are effective in lowering intraocular pressure, the primary indication of glaucoma. Human carbonic anhydrase II, and possibly carbonic anhydrase IV (CAII and CAIV, respectively), help regulate fluid secretion into the anterior chamber of the eye. Because inhibitors currently formulated as drugs to treat glaucoma were designed to target CAII, an understanding of the structural basis of CAII-CAIV discrimination by inhibitors would be useful for probing the role of each isozyme in the etiology of the disease. Here, we report the X-ray crystal structures of three novel thieno[3,2-e]-1,2-thiazine-6-sulfonamides complexed with CAII and the computationally predicted structures of the same compounds complexed with CAIV. All three compounds bind with similar affinity to CAII, but they bind with up to 100-fold lower affinities to CAIV. Comparisons of experimentally determined structures of CAII-inhibitor complexes and computationally predicted structures of CAIV-inhibitor complexes allow us to rationalize these affinity trends and outline molecular features that may contribute to high-affinity inhibitor binding to CAIV. This study demonstrates how experimental structure determination methods and computational structure prediction methods can be used together to answer questions that cannot be answered by either method alone.

Literature references that cite this PDB file's key reference

  PubMed id Reference
20116858 X.Li, S.A.Hayik, and K.M.Merz (2010).
QM/MM X-ray refinement of zinc metalloenzymes.
  J Inorg Biochem, 104, 512-522.  
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.  
17910057 A.Amini, P.J.Shrimpton, S.H.Muggleton, and M.J.Sternberg (2007).
A general approach for developing system-specific functions to score protein-ligand docked complexes using support vector inductive logic programming.
  Proteins, 69, 823-831.  
17407288 D.K.Srivastava, K.M.Jude, A.L.Banerjee, M.Haldar, S.Manokaran, J.Kooren, S.Mallik, and D.W.Christianson (2007).
Structural analysis of charge discrimination in the binding of inhibitors to human carbonic anhydrases I and II.
  J Am Chem Soc, 129, 5528-5537.
PDB codes: 2nmx 2nn1 2nn7 2nng 2nno 2nns 2nnv
16213737 G.Melagraki, A.Afantitis, H.Sarimveis, O.Igglessi-Markopoulou, and C.T.Supuran (2006).
QSAR study on para-substituted aromatic sulfonamides as carbonic anhydrase II inhibitors using topological information indices.
  Bioorg Med Chem, 14, 1108-1114.  
16506782 K.M.Jude, A.L.Banerjee, M.K.Haldar, S.Manokaran, B.Roy, S.Mallik, D.K.Srivastava, and D.W.Christianson (2006).
Ultrahigh resolution crystal structures of human carbonic anhydrases I and II complexed with "two-prong" inhibitors reveal the molecular basis of high affinity.
  J Am Chem Soc, 128, 3011-3018.
PDB codes: 2foq 2fos 2fou 2fov 2foy
14660577 D.A.Whittington, J.H.Grubb, A.Waheed, G.N.Shah, W.S.Sly, and D.W.Christianson (2004).
Expression, assay, and structure of the extracellular domain of murine carbonic anhydrase XIV: implications for selective inhibition of membrane-associated isozymes.
  J Biol Chem, 279, 7223-7228.
PDB codes: 1rj5 1rj6
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