1i90
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CARBONIC ANHYDRASE II COMPLEXED WITH AL-8520 2H-THIENO[3,2-E]-1,2-THIAZINE-6-SULFONAMIDE, 4-AMINO-3,4-DIHYDRO-2-(3-METHOXYPROPYL)-, 1,1-DIOXIDE, (R)
OverviewOverview
Carbonic anhydrase inhibitors are effective in lowering intraocular, pressure, the primary indication of glaucoma. Human carbonic anhydrase II, and possibly carbonic anhydrase IV (CAII and CAIV, respectively), help, regulate fluid secretion into the anterior chamber of the eye. Because, inhibitors currently formulated as drugs to treat glaucoma were designed, to target CAII, an understanding of the structural basis of CAII-CAIV, discrimination by inhibitors would be useful for probing the role of each, isozyme in the etiology of the disease. Here, we report the X-ray crystal, structures of three novel thieno[3,2-e]-1,2-thiazine-6-sulfonamides, complexed with CAII and the computationally predicted structures of the, same compounds complexed with CAIV. All three compounds bind with similar, affinity to CAII, but they bind with up to 100-fold lower affinities to, CAIV. Comparisons of experimentally determined structures of, CAII-inhibitor complexes and computationally predicted structures of, CAIV-inhibitor complexes allow us to rationalize these affinity trends and, outline molecular features that may contribute to high-affinity inhibitor, binding to CAIV. This study demonstrates how experimental structure, determination methods and computational structure prediction methods can, be used together to answer questions that cannot be answered by either, method alone.
DiseaseDisease
Known disease associated with this structure: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis OMIM:[611492]
About this StructureAbout this Structure
1I90 is a Single protein structure of sequence from Homo sapiens with ZN, HG and INM as ligands. Active as Carbonate dehydratase, with EC number 4.2.1.1 Full crystallographic information is available from OCA.
ReferenceReference
Structural aspects of isozyme selectivity in the binding of inhibitors to carbonic anhydrases II and IV., Kim CY, Whittington DA, Chang JS, Liao J, May JA, Christianson DW, J Med Chem. 2002 Feb 14;45(4):888-93. PMID:11831900
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