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PDBsum entry 2nmx

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protein ligands metals Protein-protein interface(s) links
Lyase PDB id
2nmx
Jmol
Contents
Protein chains
258 a.a. *
Ligands
M25 ×2
TRS
Metals
_ZN ×2
_NA
Waters ×519
* Residue conservation analysis
PDB id:
2nmx
Name: Lyase
Title: Structure of inhibitor binding to carbonic anhydrase i
Structure: Carbonic anhydrase 1. Chain: a, b. Synonym: carbonic anhydrase i, carbonate dehydratase i, ca- engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ca1. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.55Å     R-factor:   0.216     R-free:   0.248
Authors: D.W.Christianson,K.M.Jude
Key ref: D.K.Srivastava et al. (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. PubMed id: 17407288 DOI: 10.1021/ja068359w
Date:
23-Oct-06     Release date:   24-Apr-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P00915  (CAH1_HUMAN) -  Carbonic anhydrase 1
Seq:
Struc:
261 a.a.
258 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     cytoplasm   3 terms 
  Biological process     small molecule metabolic process   3 terms 
  Biochemical function     lyase activity     4 terms  

 

 
    Added reference    
 
 
DOI no: 10.1021/ja068359w J Am Chem Soc 129:5528-5537 (2007)
PubMed id: 17407288  
 
 
Structural analysis of charge discrimination in the binding of inhibitors to human carbonic anhydrases I and II.
D.K.Srivastava, K.M.Jude, A.L.Banerjee, M.Haldar, S.Manokaran, J.Kooren, S.Mallik, D.W.Christianson.
 
  ABSTRACT  
 
Despite the similarity in the active site pockets of carbonic anhydrase (CA) isozymes I and II, the binding affinities of benzenesulfonamide inhibitors are invariably higher with CA II as compared to CA I. To explore the structural basis of this molecular recognition phenomenon, we have designed and synthesized simple benzenesulfonamide inhibitors substituted at the para position with positively charged, negatively charged, and neutral functional groups, and we have determined the affinities and X-ray crystal structures of their enzyme complexes. The para-substituents are designed to bind in the midsection of the 15 A deep active site cleft, where interactions with enzyme residues and solvent molecules are possible. We find that a para-substituted positively charged amino group is more poorly tolerated in the active site of CA I compared with CA II. In contrast, a para-substituted negatively charged carboxylate substituent is tolerated equally well in the active sites of both CA isozymes. Notably, enzyme-inhibitor affinity increases upon neutralization of inhibitor charged groups by amidation or esterification. These results inform the design of short molecular linkers connecting the benzenesulfonamide group and a para-substituted tail group in "two-prong" CA inhibitors: an optimal linker segment will be electronically neutral, yet capable of engaging in at least some hydrogen bond interactions with protein residues and/or solvent. Microcalorimetric data reveal that inhibitor binding to CA I is enthalpically less favorable and entropically more favorable than inhibitor binding to CA II. This contrasting behavior may arise in part from differences in active site desolvation and the conformational entropy of inhibitor binding to each isozyme active site.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21420862 N.Pala, R.Dallocchio, A.Dessì, A.Brancale, F.Carta, S.Ihm, A.Maresca, M.Sechi, and C.T.Supuran (2011).
Virtual screening-driven identification of human carbonic anhydrase inhibitors incorporating an original, new pharmacophore.
  Bioorg Med Chem Lett, 21, 2515-2520.  
20445237 C.A.Behnke, I.Le Trong, J.W.Godden, E.A.Merritt, D.C.Teller, J.Bajorath, and R.E.Stenkamp (2010).
Atomic resolution studies of carbonic anhydrase II.
  Acta Crystallogr D Biol Crystallogr, 66, 616-627.
PDB codes: 1lug 3k34
20505865 V.Alterio, S.M.Monti, E.Truppo, C.Pedone, C.T.Supuran, and G.De Simone (2010).
The first example of a significant active site conformational rearrangement in a carbonic anhydrase-inhibitor adduct: the carbonic anhydrase I-topiramate complex.
  Org Biomol Chem, 8, 3528-3533.
PDB code: 3lxe
19882701 A.D.Scott, C.Phillips, A.Alex, M.Flocco, A.Bent, A.Randall, R.O'Brien, L.Damian, and L.H.Jones (2009).
Thermodynamic Optimisation in Drug Discovery: A Case Study using Carbonic Anhydrase Inhibitors.
  ChemMedChem, 4, 1985-1989.
PDB codes: 2weg 2weh 2wej 2weo
19226504 I.Miyazaki, S.Simizu, K.Ishida, and H.Osada (2009).
On-chip fragment-based approach for discovery of high-affinity bivalent inhibitors.
  Chembiochem, 10, 838-843.  
19140795 J.M.Chambers, P.A.Hill, J.A.Aaron, Z.Han, D.W.Christianson, N.N.Kuzma, and I.J.Dmochowski (2009).
Cryptophane xenon-129 nuclear magnetic resonance biosensors targeting human carbonic anhydrase.
  J Am Chem Soc, 131, 563-569.  
  19851004 K.H.Sippel, A.H.Robbins, J.Domsic, C.Genis, M.Agbandje-McKenna, and R.McKenna (2009).
High-resolution structure of human carbonic anhydrase II complexed with acetazolamide reveals insights into inhibitor drug design.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 65, 992-995.
PDB code: 3hs4
19330012 S.Tsukiji, M.Miyagawa, Y.Takaoka, T.Tamura, and I.Hamachi (2009).
Ligand-directed tosyl chemistry for protein labeling in vivo.
  Nat Chem Biol, 5, 341-343.  
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.  
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.