PDBsum entry 1jcz

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protein ligands metals Protein-protein interface(s) links
Lyase PDB id
Protein chain
260 a.a. *
ACY ×2
_ZN ×2
Waters ×537
* Residue conservation analysis
PDB id:
Name: Lyase
Title: Crystal structure of the extracellular domain of human carbo anhydrase xii
Structure: Carbonic anhydrase xii. Chain: a, b. Fragment: extracellular domain. Synonym: carbonate dehydratase xii, ca-xii, tumor antigen h 3.1.3. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Tetramer (from PQS)
1.55Å     R-factor:   0.194     R-free:   0.221
Authors: D.A.Whittington,A.Waheed,B.Ulmasov,G.N.Shah,J.H.Grubb,W.S.Sl D.W.Christianson
Key ref:
D.A.Whittington et al. (2001). Crystal structure of the dimeric extracellular domain of human carbonic anhydrase XII, a bitopic membrane protein overexpressed in certain cancer tumor cells. Proc Natl Acad Sci U S A, 98, 9545-9550. PubMed id: 11493685 DOI: 10.1073/pnas.161301298
11-Jun-01     Release date:   17-Aug-01    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
O43570  (CAH12_HUMAN) -  Carbonic anhydrase 12
354 a.a.
260 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
Bound ligand (Het Group name = ACY)
matches with 75.00% similarity
+ 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     integral to membrane   1 term 
  Biological process     one-carbon metabolic process   1 term 
  Biochemical function     carbonate dehydratase activity     2 terms  


    Added reference    
DOI no: 10.1073/pnas.161301298 Proc Natl Acad Sci U S A 98:9545-9550 (2001)
PubMed id: 11493685  
Crystal structure of the dimeric extracellular domain of human carbonic anhydrase XII, a bitopic membrane protein overexpressed in certain cancer tumor cells.
D.A.Whittington, A.Waheed, B.Ulmasov, G.N.Shah, J.H.Grubb, W.S.Sly, D.W.Christianson.
Overexpression of the zinc enzyme carbonic anhydrase (CA; EC ) XII is observed in certain human cancers. This bitopic membrane protein contains an N-terminal extracellular catalytic domain, a membrane-spanning alpha-helix, and a small intracellular C-terminal domain. We have determined the three-dimensional structure of the extracellular catalytic domain of human CA XII by x-ray crystallographic methods at 1.55-A resolution. The structure reveals a prototypical CA fold; however, two CA XII domains associate to form an isologous dimer, an observation that is confirmed by studies of the enzyme in solution. The identification of signature GXXXG and GXXXS motifs in the transmembrane sequence that facilitate helix-helix association is additionally consistent with dimeric architecture. The dimer interface is situated so that the active site clefts of each monomer are clearly exposed on one face of the dimer, and the C termini are located together on the opposite face of the dimer to facilitate membrane interaction. The amino acid composition of the active-site cleft closely resembles that of the other CA isozymes in the immediate vicinity of the catalytic zinc ion, but differs in the region of the nearby alpha-helical "130's segment." The structure of the CA XII-acetazolamide complex is also reported at 1.50-A resolution, and prospects for the design of CA XII-specific inhibitors of possible chemotherapeutic value are discussed.
  Selected figure(s)  
Figure 3.
Fig. 3. Schematic drawing showing the CA XII dimer in the membrane; orientation is the same as that in Fig. 2. The extracellular CA domains (molecules A and B) are colored blue and green, respectively. Zinc ions appear as white spheres, disulfide linkages are yellow, and acetazolamide molecules appear as balls-and-sticks. The yellow transmembrane helices are modeled after the structure of the glycophorin A dimer reported by MacKenzie and colleagues (42): both CA XII and glycophorin A contain transmembrane GXXXG dimerization motifs (40, 41). The intracellular C-terminal domains appear as orange spheres. These domains contain potential phosphorylation sites but are currently of unknown structure. Note that membrane association orients the enzyme active sites toward the extracellular milieu, poised for catalysis.
Figure 4.
Fig. 4. The active site of the native CA XII structure showing the five-coordinate zinc ion. The zinc ion is colored cyan. Oxygen, nitrogen, and carbon atoms are red, blue, and gray, respectively. Hydrogen bonds are shown as dashed lines with distances labeled (Å). Average zinc-ligand distances are as follows: Zn2+-His-94, 2.0 Å; Zn2+-His-96, 2.1 Å; Zn2+-His-119, 2.1 Å; Zn2+-OH[2], 2.1 Å; Zn2+-acetate, 2.3 Å.
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21298264 C.Battke, E.Kremmer, J.Mysliwietz, G.Gondi, C.Dumitru, S.Brandau, S.Lang, D.Vullo, C.Supuran, and R.Zeidler (2011).
Generation and characterization of the first inhibitory antibody targeting tumour-associated carbonic anhydrase XII.
  Cancer Immunol Immunother, 60, 649-658.  
21184099 E.Muhammad, N.Leventhal, G.Parvari, A.Hanukoglu, I.Hanukoglu, V.Chalifa-Caspi, Y.Feinstein, J.Weinbrand, H.Jacoby, E.Manor, T.Nagar, J.C.Beck, V.C.Sheffield, E.Hershkovitz, and R.Parvari (2011).
Autosomal recessive hyponatremia due to isolated salt wasting in sweat associated with a mutation in the active site of Carbonic Anhydrase 12.
  Hum Genet, 129, 397-405.  
21377464 J.A.Cuesta-Seijo, M.S.Borchert, J.C.Navarro-Poulsen, K.M.Schnorr, S.B.Mortensen, and L.Lo Leggio (2011).
Structure of a dimeric fungal α-type carbonic anhydrase.
  FEBS Lett, 585, 1042-1048.  
20015196 J.Chiche, M.C.Brahimi-Horn, and J.Pouysségur (2010).
Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer.
  J Cell Mol Med, 14, 771-794.  
20133774 S.Bouyain, and D.J.Watkins (2010).
The protein tyrosine phosphatases PTPRZ and PTPRG bind to distinct members of the contactin family of neural recognition molecules.
  Proc Natl Acad Sci U S A, 107, 2443-2448.
PDB codes: 3jxa 3jxf 3jxg 3jxh 3kld
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
19805286 V.Alterio, M.Hilvo, A.Di Fiore, C.T.Supuran, P.Pan, S.Parkkila, A.Scaloni, J.Pastorek, S.Pastorekova, C.Pedone, A.Scozzafava, S.M.Monti, and G.De Simone (2009).
Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX.
  Proc Natl Acad Sci U S A, 106, 16233-16238.
PDB code: 3iai
18444244 H.Y.Dai, C.C.Hong, S.C.Liang, M.D.Yan, G.M.Lai, A.L.Cheng, and S.E.Chuang (2008).
Carbonic anhydrase III promotes transformation and invasion capability in hepatoma cells through FAK signaling pathway.
  Mol Carcinog, 47, 956-963.  
18322268 J.Haapasalo, M.Hilvo, K.Nordfors, H.Haapasalo, S.Parkkila, A.Hyrskyluoto, I.Rantala, A.Waheed, W.S.Sly, S.Pastorekova, J.Pastorek, and A.K.Parkkila (2008).
Identification of an alternatively spliced isoform of carbonic anhydrase XII in diffusely infiltrating astrocytic gliomas.
  Neuro Oncol, 10, 131-138.  
18161740 K.D'Ambrosio, B.Masereel, A.Thiry, A.Scozzafava, C.T.Supuran, and G.De Simone (2008).
Carbonic anhydrase inhibitors: binding of indanesulfonamides to the human isoform II.
  ChemMedChem, 3, 473-477.
PDB codes: 2qo8 2qoa
  19956789 S.Manokaran, A.Berg, X.Zhang, W.Chen, and D.K.Srivastava (2008).
Modulation of Ligand Binding Affinity of Tumorigenic Carbonic Anhydrase XII upon Interaction with Cationic CdTe Quantum Dots.
  J Biomed Nanotechnol, 4, 491-498.  
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.  
17607683 A.Thiry, B.Masereel, J.M.Dogné, C.T.Supuran, J.Wouters, and C.Michaux (2007).
Exploration of the Binding Mode of Indanesulfonamides as Selective Inhibitors of Human Carbonic Anhydrase Type VII by Targeting Lys 91.
  ChemMedChem, 2, 1273-1280.  
15894606 L.Premkumar, H.M.Greenblatt, U.K.Bageshwar, T.Savchenko, I.Gokhman, J.L.Sussman, and A.Zamir (2005).
Three-dimensional structure of a halotolerant algal carbonic anhydrase predicts halotolerance of a mammalian homolog.
  Proc Natl Acad Sci U S A, 102, 7493-7498.
PDB code: 1y7w
14983512 P.Halmi, J.Lehtonen, A.Waheed, W.S.Sly, and S.Parkkila (2004).
Expression of hypoxia-inducible, membrane-bound carbonic anhydrase isozyme XII in mouse tissues.
  Anat Rec A Discov Mol Cell Evol Biol, 277, 171-177.  
12832778 L.Haue, P.A.Pedersen, P.L.Jorgensen, and K.O.Håkansson (2003).
Cloning, expression, purification and crystallization of the N-domain from the alpha(2) subunit of the membrane-spanning Na,K-ATPase protein.
  Acta Crystallogr D Biol Crystallogr, 59, 1259-1261.  
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.