PDBsum entry 1znc

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protein ligands metals Protein-protein interface(s) links
Lyase PDB id
Protein chains
262 a.a. *
247 a.a. *
SO4 ×2
_ZN ×2
Waters ×32
* Residue conservation analysis
PDB id:
Name: Lyase
Title: Human carbonic anhydrase iv
Structure: Carbonic anhydrase iv. Chain: a, b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: human caiv. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: cho-cells.
2.80Å     R-factor:   0.197     R-free:   0.252
Authors: T.Stams,D.W.Christianson
Key ref: T.Stams et al. (1996). Crystal structure of the secretory form of membrane-associated human carbonic anhydrase IV at 2.8-A resolution. Proc Natl Acad Sci U S A, 93, 13589-13594. PubMed id: 8942978
17-Sep-96     Release date:   17-Sep-97    
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Protein chain
Pfam   ArchSchema ?
P22748  (CAH4_HUMAN) -  Carbonic anhydrase 4
312 a.a.
262 a.a.
Protein chain
Pfam   ArchSchema ?
P22748  (CAH4_HUMAN) -  Carbonic anhydrase 4
312 a.a.
247 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, B: 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     cell surface   19 terms 
  Biological process     small molecule metabolic process   6 terms 
  Biochemical function     protein binding     5 terms  


    Added reference    
Proc Natl Acad Sci U S A 93:13589-13594 (1996)
PubMed id: 8942978  
Crystal structure of the secretory form of membrane-associated human carbonic anhydrase IV at 2.8-A resolution.
T.Stams, S.K.Nair, T.Okuyama, A.Waheed, W.S.Sly, D.W.Christianson.
It has recently been demonstrated that the C-terminal deletion mutant of recombinant human carbonic anhydrase IV (G267X CA IV) converts the normally glycosylphosphatidylinositol-anchored enzyme into a soluble secretory form which has the same catalytic properties as the membrane-associated enzyme purified from human tissues. We have determined the three-dimensional structure of the secretory form of human CA IV by x-ray crystallographic methods to a resolution of 2.8 A. Although the zinc binding site and the hydrophobic substrate binding pocket of CA IV are generally similar to those of other mammalian isozymes, unique structural differences are found elsewhere in the active site. Two disufide linkages, Cys-6-Cys-11G and Cys-23-Cys-203, stabilize the conformation of the N-terminal domain. The latter disulfide additionally stabilizes an active site loop containing a cis-peptide linkage between Pro-201 and Thr-202 (this loop contains catalytic residue Thr-199). On the opposite side of the active site, the Val-131-Asp-136 segment adopts an extended loop conformation instead of an alpha-helix conformation as found in other isozymes. Finally, the C terminus is surrounded by a substantial electropositive surface potential, which is likely to stabilize the interaction of CA IV with the negatively charged phospholipid headgroups of the membrane. These structural features are unique to CA IV and provide a framework for the design of sulfonamide inhibitors selective for this particular isozyme.

Literature references that cite this PDB file's key reference

  PubMed id Reference
20626030 A.Pandor, R.Ramesar, and S.Prince (2010).
Cell-specific differences in the processing of the R14W CAIV mutant associated with retinitis pigmentosa 17.
  J Cell Biochem, 111, 735-741.  
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
19211803 R.Datta, A.Waheed, G.Bonapace, G.N.Shah, and W.S.Sly (2009).
Pathogenesis of retinitis pigmentosa associated with apoptosis-inducing mutations in carbonic anhydrase IV.
  Proc Natl Acad Sci U S A, 106, 3437-3442.  
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
18931408 J.Jeyakanthan, S.Rangarajan, P.Mridula, S.P.Kanaujia, Y.Shiro, S.Kuramitsu, S.Yokoyama, and K.Sekar (2008).
Observation of a calcium-binding site in the gamma-class carbonic anhydrase from Pyrococcus horikoshii.
  Acta Crystallogr D Biol Crystallogr, 64, 1012-1019.
PDB codes: 1v3w 1v67 2fko
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.  
15647194 I.Nishimori, E.Miyaji, K.Morimoto, K.Nagao, M.Kamada, and S.Onishi (2005).
Serum antibodies to carbonic anhydrase IV in patients with autoimmune pancreatitis.
  Gut, 54, 274-281.  
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
15295099 G.Bonapace, A.Waheed, G.N.Shah, and W.S.Sly (2004).
Chemical chaperones protect from effects of apoptosis-inducing mutation in carbonic anhydrase IV identified in retinitis pigmentosa 17.
  Proc Natl Acad Sci U S A, 101, 12300-12305.  
14567693 B.V.Alvarez, F.B.Loiselle, C.T.Supuran, G.J.Schwartz, and J.R.Casey (2003).
Direct extracellular interaction between carbonic anhydrase IV and the human NBC1 sodium/bicarbonate co-transporter.
  Biochemistry, 42, 12321-12329.  
12500287 C.T.Supuran, A.Scozzafava, and A.Casini (2003).
Carbonic anhydrase inhibitors.
  Med Res Rev, 23, 146-189.  
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.  
12009884 M.Ferraroni, S.Tilli, F.Briganti, W.R.Chegwidden, C.T.Supuran, K.E.Wiebauer, R.E.Tashian, and A.Scozzafava (2002).
Crystal structure of a zinc-activated variant of human carbonic anhydrase I, CA I Michigan 1: evidence for a second zinc binding site involving arginine coordination.
  Biochemistry, 41, 6237-6244.
PDB codes: 1j9w 1jv0
11493685 D.A.Whittington, A.Waheed, B.Ulmasov, G.N.Shah, J.H.Grubb, W.S.Sly, and D.W.Christianson (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.
PDB codes: 1jcz 1jd0
10978542 K.S.Smith, and J.G.Ferry (2000).
Prokaryotic carbonic anhydrases.
  FEMS Microbiol Rev, 24, 335-366.  
11073902 K.S.Smith, N.J.Cosper, C.Stalhandske, R.A.Scott, and J.G.Ferry (2000).
Structural and kinetic characterization of an archaeal beta-class carbonic anhydrase.
  J Bacteriol, 182, 6605-6613.  
10924115 T.M.Iverson, B.E.Alber, C.Kisker, J.G.Ferry, and D.C.Rees (2000).
A closer look at the active site of gamma-class carbonic anhydrases: high-resolution crystallographic studies of the carbonic anhydrase from Methanosarcina thermophila.
  Biochemistry, 39, 9222-9231.
PDB codes: 1qq0 1qre 1qrf 1qrg 1qrl 1qrm
  10515911 K.S.Smith, and J.G.Ferry (1999).
A plant-type (beta-class) carbonic anhydrase in the thermophilic methanoarchaeon Methanobacterium thermoautotrophicum.
  J Bacteriol, 181, 6247-6253.  
9667939 J.E.Coleman (1998).
Zinc enzymes.
  Curr Opin Chem Biol, 2, 222-234.  
  9541386 T.Stams, Y.Chen, P.A.Boriack-Sjodin, J.D.Hurt, J.Liao, J.A.May, T.Dean, P.Laipis, D.N.Silverman, and D.W.Christianson (1998).
Structures of murine carbonic anhydrase IV and human carbonic anhydrase II complexed with brinzolamide: molecular basis of isozyme-drug discrimination.
  Protein Sci, 7, 556-563.
PDB codes: 1a42 2znc 3znc
9265618 F.Briganti, S.Mangani, P.Orioli, A.Scozzafava, G.Vernaglione, and C.T.Supuran (1997).
Carbonic anhydrase activators: X-ray crystallographic and spectroscopic investigations for the interaction of isozymes I and II with histamine.
  Biochemistry, 36, 10384-10392.
PDB code: 1avn
9336168 N.Ben-Tal, B.Honig, C.Miller, and S.McLaughlin (1997).
Electrostatic binding of proteins to membranes. Theoretical predictions and experimental results with charybdotoxin and phospholipid vesicles.
  Biophys J, 73, 1717-1727.  
9054574 T.T.Baird, A.Waheed, T.Okuyama, W.S.Sly, and C.A.Fierke (1997).
Catalysis and inhibition of human carbonic anhydrase IV.
  Biochemistry, 36, 2669-2678.  
8942988 S.Tamai, A.Waheed, L.B.Cody, and W.S.Sly (1996).
Gly-63-->Gln substitution adjacent to His-64 in rodent carbonic anhydrase IVs largely explains their reduced activity.
  Proc Natl Acad Sci U S A, 93, 13647-13652.  
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 code is shown on the right.