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PDBsum entry 1a42

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protein ligands metals links
Lyase PDB id
1a42
Jmol PyMol
Contents
Protein chain
256 a.a. *
Ligands
BZU
Metals
_HG
_ZN
Waters ×55
* Residue conservation analysis
PDB id:
1a42
Name: Lyase
Title: Human carbonic anhydrase ii complexed with brinzolamide
Structure: Carbonic anhydrase ii. Chain: a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: human caii. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.25Å     R-factor:   not given    
Authors: P.A.Boriack-Sjodin,D.W.Christianson
Key ref:
T.Stams et al. (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. PubMed id: 9541386 DOI: 10.1002/pro.5560070303
Date:
10-Feb-98     Release date:   23-Mar-99    
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  - Carbonic anhydrase.
[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   22 terms 
  Biochemical function     protein binding     6 terms  

 

 
    Added reference    
 
 
DOI no: 10.1002/pro.5560070303 Protein Sci 7:556-563 (1998)
PubMed id: 9541386  
 
 
Structures of murine carbonic anhydrase IV and human carbonic anhydrase II complexed with brinzolamide: molecular basis of isozyme-drug discrimination.
T.Stams, Y.Chen, P.A.Boriack-Sjodin, J.D.Hurt, J.Liao, J.A.May, T.Dean, P.Laipis, D.N.Silverman, D.W.Christianson.
 
  ABSTRACT  
 
Carbonic anhydrase IV (CAIV) is a membrane-associated enzyme anchored to plasma membrane surfaces by a phosphatidylinositol glycan linkage. We have determined the 2.8-angstroms resolution crystal structure of a truncated, soluble form of recombinant murine CAIV. We have also determined the structure of its complex with a drug used for glaucoma therapy, the sulfonamide inhibitor brinzolamide (Azopt). The overall structure of murine CAIV is generally similar to that of human CAIV; however, some local structural differences are found in the active site resulting from amino acid sequence differences in the "130's segment" and the residue-63 loop (these may affect the nearby catalytic proton shuttle, His-64). Similar to human CAIV, the C-terminus of murine CAIV is surrounded by a substantial electropositive surface potential that may stabilize the interaction with the phospholipid membrane. Binding interactions observed for brinzolamide rationalize the generally weaker affinity of inhibitors used in glaucoma therapy toward CAIV compared with CAII.
 
  Selected figure(s)  
 
Figure 6.
Fig. 6. Differenceelectrondensitymap of thehumanCAII-brinzolamide complex,generatedwithFouriercoefficients IF,I - I,] nd phasescal- culatedfromthefnalmodelminustheatoms of brinzolamide(contoured at 3~ ). Thesulfonamidenitrogen of brinzolamide coordinates tozncand displaces zinc-boundhydroxide,therebymaintainingtetrahedralmetalco- ordinationgeometry.Thealiphatictail of brinzolamidemakesvander Waals contactwihPhe-131and Pro-202.
Figure 8.
Fig. 8. CAII-brinzolamide and CAIV-brinzolamide complexes (upper left and lower right, respectively). Brinzolamide is magenta; the CAIV- membrane interaction is represented schematically, where the GPI anchor (yellow) attached to the C-terminus of the enzyme is inserted into the CAIV orientation by interacting with negatively charged phosphates (red). Figure prepared with MOLSCRIPT (Kraulis, 1991) and Raster 3D (Bacon & Anderson, 1988; Merritt & Murphy, 1994).
 
  The above figures are reprinted from an Open Access publication published by the Protein Society: Protein Sci (1998, 7, 556-563) copyright 1998.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  20463789 A.M.Moss, A.Harris, B.Siesky, D.Rusia, K.M.Williamson, and Y.Shoshani (2010).
Update and critical appraisal of combined timolol and carbonic anhydrase inhibitors and the effect on ocular blood flow in glaucoma patients.
  Clin Ophthalmol, 4, 233-241.  
19348600 A.Martínez, and M.Sánchez-Salorio (2009).
A comparison of the long-term effects of dorzolamide 2% and brinzolamide 1%, each added to timolol 0.5%, on retrobulbar hemodynamics and intraocular pressure in open-angle glaucoma patients.
  J Ocul Pharmacol Ther, 25, 239-248.  
  19467155 J.M.Liefhebber, B.W.Brandt, R.Broer, W.J.Spaan, and H.C.van Leeuwen (2009).
Hepatitis C virus NS4B carboxy terminal domain is a membrane binding domain.
  Virol J, 6, 62.  
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
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.  
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
17284800 K.Ravikumar, and B.Sridhar (2007).
Dorzolamide hydrochloride: an antiglaucoma agent.
  Acta Crystallogr C, 63, o108-o110.  
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
15939021 L.W.Yang, and I.Bahar (2005).
Coupling between catalytic site and collective dynamics: a requirement for mechanochemical activity of enzymes.
  Structure, 13, 893-904.  
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
11121027 B.Ulmasov, A.Waheed, G.N.Shah, J.H.Grubb, W.S.Sly, C.Tu, and D.N.Silverman (2000).
Purification and kinetic analysis of recombinant CA XII, a membrane carbonic anhydrase overexpressed in certain cancers.
  Proc Natl Acad Sci U S A, 97, 14212-14217.  
10944213 O.Dym, E.A.Pratt, C.Ho, and D.Eisenberg (2000).
The crystal structure of D-lactate dehydrogenase, a peripheral membrane respiratory enzyme.
  Proc Natl Acad Sci U S A, 97, 9413-9418.
PDB code: 1f0x
  9865942 P.A.Boriack-Sjodin, S.Zeitlin, H.H.Chen, L.Crenshaw, S.Gross, A.Dantanarayana, P.Delgado, J.A.May, T.Dean, and D.W.Christianson (1998).
Structural analysis of inhibitor binding to human carbonic anhydrase II.
  Protein Sci, 7, 2483-2489.
PDB codes: 1bn1 1bn3 1bn4 1bnm 1bnn 1bnq 1bnt 1bnu 1bnv 1bnw
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.

 

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