PDBsum entry 1bnn

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Lyase PDB id
Protein chain
257 a.a.
Waters ×99

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Key reference
Title Structural analysis of inhibitor binding to human carbonic anhydrase ii.
Authors 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.
Ref. Protein Sci, 1998, 7, 2483-2489. [DOI no: 10.1002/pro.5560071201]
PubMed id 9865942
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.
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.
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.
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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