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PDBsum entry 1bnm
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* Residue conservation analysis
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Enzyme class 2:
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E.C.4.2.1.1
- carbonic anhydrase.
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Reaction:
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hydrogencarbonate + H+ = CO2 + H2O
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hydrogencarbonate
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+
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H(+)
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=
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CO2
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+
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H2O
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Cofactor:
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Zn(2+)
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Enzyme class 3:
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E.C.4.2.1.69
- cyanamide hydratase.
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Reaction:
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urea = cyanamide + H2O
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urea
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=
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cyanamide
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+
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H2O
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Note, where more than one E.C. class is given (as above), each may
correspond to a different protein domain or, in the case of polyprotein
precursors, to a different mature protein.
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Protein Sci
7:2483-2489
(1998)
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PubMed id:
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Structural analysis of inhibitor binding to human carbonic anhydrase II.
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P.A.Boriack-Sjodin,
S.Zeitlin,
H.H.Chen,
L.Crenshaw,
S.Gross,
A.Dantanarayana,
P.Delgado,
J.A.May,
T.Dean,
D.W.Christianson.
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ABSTRACT
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X-ray crystal structures of carbonic anhydrase II (CAII) complexed with
sulfonamide inhibitors illuminate the structural determinants of high affinity
binding in the nanomolar regime. The primary binding interaction is the
coordination of a primary sulfonamide group to the active site zinc ion.
Secondary interactions fine-tune tight binding in regions of the active site
cavity >5 A away from zinc, and this work highlights three such features: (1)
advantageous conformational restraints of a bicyclic
thienothiazene-6-sulfonamide-1,1-dioxide inhibitor skeleton in comparison with a
monocyclic 2,5-thiophenedisulfonamide skeleton; (2) optimal substituents
attached to a secondary sulfonamide group targeted to interact with hydrophobic
patches defined by Phe131, Leu198, and Pro202; and (3) optimal stereochemistry
and configuration at the C-4 position of bicyclic thienothiazene-6-sulfonamides;
the C-4 substituent can interact with His64, the catalytic proton shuttle.
Structure-activity relationships rationalize affinity trends observed during the
development of brinzolamide (Azopt), the newest carbonic anhydrase inhibitor
approved for the treatment of glaucoma.
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Selected figure(s)
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Figure 3.
Fig. 3. Superposition of theatomiccoordinates of AL5300 (gree)and
AL5415 (red).Forclarity, only theproteinatoms of CAII inthe CAII-
AL5415complexareshown Primarysulfonamide-zinccoordi-
nationgeometry,andedge-to-faceinteractionsbetweenthethophene ``tail''
of theinhibitorand Phel31, areidenticalinthetwo complees. Binding
differenceare localized totheConformationofthesecondarysulfonamide
group.
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Figure 6.
Fig. 6. Superpositionoftheatomiccoordinatesofbrinzolamide(Azoptm;
AL4862, Kd = 0.13 nM) anddorzolamide(Trusoptm, Ki 0.37 nM, Greer
et l., 994; Smithet al., 1994). thetwonewest CAII inhibitorsappoved
for the treatmentofglaucoma.Brinzolamideisred;dorzolaide is green.
Forclarity,onlytheproteinatomsoCAII in the CAII-L4862 (brizola-
mide)complex are shown(yellow).Notethatthesix-memberedthiazene
ring of rizolamideadopts a half-chair,conformation,whereasthesix-
membeedthienoringofdorzolamideadopts a half-chair2conformation.
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The above figures are
reprinted
from an Open Access publication published by the Protein Society:
Protein Sci
(1998,
7,
2483-2489)
copyright 1998.
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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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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.
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Chem Rev,
108,
946.
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A.Amini,
P.J.Shrimpton,
S.H.Muggleton,
and
M.J.Sternberg
(2007).
A general approach for developing system-specific functions to score protein-ligand docked complexes using support vector inductive logic programming.
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Proteins,
69,
823-831.
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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.
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J Am Chem Soc,
128,
3011-3018.
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PDB codes:
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M.Kontoyianni,
G.S.Sokol,
and
L.M.McClellan
(2005).
Evaluation of library ranking efficacy in virtual screening.
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J Comput Chem,
26,
11-22.
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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.
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Proc Natl Acad Sci U S A,
98,
9545-9550.
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PDB codes:
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S.Grüneberg,
B.Wendt,
and
G.Klebe
(2001).
Subnanomolar Inhibitors from Computer Screening: A Model Study Using Human Carbonic Anhydrase II.
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Angew Chem Int Ed Engl,
40,
389-393.
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J.Shimada,
A.V.Ishchenko,
and
E.I.Shakhnovich
(2000).
Analysis of knowledge-based protein-ligand potentials using a self-consistent method.
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Protein Sci,
9,
765-775.
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M.F.Sugrue
(2000).
Pharmacological and ocular hypotensive properties of topical carbonic anhydrase inhibitors.
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Prog Retin Eye Res,
19,
87.
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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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Links
