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PDBsum entry 1bnm
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References listed in PDB file
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Key reference
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Title
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Structural analysis of inhibitor binding to human carbonic anhydrase ii.
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Authors
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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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Ref.
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Protein Sci, 1998,
7,
2483-2489.
[DOI no: ]
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PubMed id
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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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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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