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PDBsum entry 2h15

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protein ligands metals links
Lyase PDB id
2h15
Jmol
Contents
Protein chain
256 a.a. *
Ligands
B19
Metals
_ZN
_HG
Waters ×182
* Residue conservation analysis
PDB id:
2h15
Name: Lyase
Title: Carbonic anhydrase inhibitors: clashing with ala65 as a means of designing isozyme-selective inhibitors that show low affinity for the ubiquitous isozyme ii
Structure: Carbonic anhydrase 2. Chain: a. Synonym: carbonic anhydrase ii, carbonate dehydratase ii, ca-ii, carbonic anhydrasE C. Ec: 4.2.1.1
Source: Homo sapiens. Human. Organism_taxid: 9606
Resolution:
1.90Å     R-factor:   0.188     R-free:   0.225
Authors: J.Y.Winum,C.Temperini,S.Ciattini,A.Scozzafava,C.T.Supuran
Key ref: J.Y.Winum et al. (2006). Carbonic anhydrase inhibitors: clash with Ala65 as a means for designing inhibitors with low affinity for the ubiquitous isozyme II, exemplified by the crystal structure of the topiramate sulfamide analogue. J Med Chem, 49, 7024-7031. PubMed id: 17125255 DOI: 10.1021/jm060807n
Date:
16-May-06     Release date:   27-Mar-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00918  (CAH2_HUMAN) -  Carbonic anhydrase 2
Seq:
Struc:
260 a.a.
256 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: 10.1021/jm060807n J Med Chem 49:7024-7031 (2006)
PubMed id: 17125255  
 
 
Carbonic anhydrase inhibitors: clash with Ala65 as a means for designing inhibitors with low affinity for the ubiquitous isozyme II, exemplified by the crystal structure of the topiramate sulfamide analogue.
J.Y.Winum, C.Temperini, K.El Cheikh, A.Innocenti, D.Vullo, S.Ciattini, J.L.Montero, A.Scozzafava, C.T.Supuran.
 
  ABSTRACT  
 
The sulfamide analogue of the antiepileptic drug topiramate is a 210 times less potent inhibitor of isozyme II of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) compared to topiramate but effectively inhibits isozymes CA VA, VB, VII, XIII, and XIV (KI in the range of 21-35 nM). Its weak binding to CA II is due to a clash between one methyl group of the inhibitor and Ala65 and may be exploited for the drug design of compounds with lower affinity for this ubiquitous isozyme, as Ala65 is unique to CA II. As shown by X-ray crystallography, the sulfamide analogue binds to CA II with the deprotonated sulfamide moiety coordinated to Zn(II) and with the organic scaffold making an extended network of hydrogen bonds with Thr199, Gln92, His94, Asn62, and Thr200. Its binding to this isozyme is more similar to that of topiramate and quite different from that of the topiramate cyclic sulfate analogue RWJ-37947.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
22590438 M.Xie, S.S.Shen, B.F.Chen, and Y.Sha (2012).
[(3aS,5aR,8aR,8bS)-2,2,7,7-Tetra-methyl-tetra-hydro-3aH-bis-[1,3]dioxolo[4,5-b:4',5'-d]pyran-3a-yl]methyl (R)-N-(1-phenyl-eth-yl)sulfamate.
  Acta Crystallogr Sect E Struct Rep Online, 68, o1581.  
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
21470859 M.Rami, A.Maresca, F.Z.Smaine, J.L.Montero, A.Scozzafava, J.Y.Winum, and C.T.Supuran (2011).
Sulfonamides incorporating boroxazolidone moieties are potent inhibitors of the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII.
  Bioorg Med Chem Lett, 21, 2975-2979.  
20448906 C.Wong, R.J.Griffin, I.R.Hardcastle, J.S.Northen, L.Z.Wang, and B.T.Golding (2010).
Synthesis of sulfonamide-based kinase inhibitors from sulfonates by exploiting the abrogated SN2 reactivity of 2,2,2-trifluoroethoxysulfonates.
  Org Biomol Chem, 8, 2457-2464.  
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
19058143 J.Y.Winum, S.A.Poulsen, and C.T.Supuran (2009).
Therapeutic applications of glycosidic carbonic anhydrase inhibitors.
  Med Res Rev, 29, 419-435.  
18167490 C.T.Supuran (2008).
Carbonic anhydrases: novel therapeutic applications for inhibitors and activators.
  Nat Rev Drug Discov, 7, 168-181.  
17880011 J.Y.Winum, M.Rami, A.Scozzafava, J.L.Montero, and C.Supuran (2008).
Carbonic anhydrase IX: a new druggable target for the design of antitumor agents.
  Med Res Rev, 28, 445-463.  
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.  
17877442 D.Vega, N.M.Maalouf, and K.Sakhaee (2007).
Increased propensity for calcium phosphate kidney stones with topiramate use.
  Expert Opin Drug Saf, 6, 547-557.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.