6xxt | pdb_00006xxt
The crystal structure of hCA II in complex with a 4-(4-aroylpiperazine-1-carbonyl)benzenesulfonamide derivative.
Structural highlights
DiseaseCAH2_HUMAN Defects in CA2 are the cause of osteopetrosis autosomal recessive type 3 (OPTB3) [MIM:259730; also known as osteopetrosis with renal tubular acidosis, carbonic anhydrase II deficiency syndrome, Guibaud-Vainsel syndrome or marble brain disease. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. The disorder occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Autosomal recessive osteopetrosis is usually associated with normal or elevated amount of non-functional osteoclasts. OPTB3 is associated with renal tubular acidosis, cerebral calcification (marble brain disease) and in some cases with mental retardation.[1] [2] [3] [4] [5] FunctionCAH2_HUMAN Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye.[6] [7] Publication Abstract from PubMedWe report the synthesis and biochemical evaluation of a series of substituted 4-(4-aroylpiperazine-1-carbonyl)benzenesulfonamides (5a-s) developed as inhibitors of druggable carbonic anhydrase (CA) isoforms, as tools for the identification of new therapeutics. X-ray crystallography confirmed that this class of benzenesulfonamides binds CAs through the canonical anchoring of the benzenesulfonamide moiety to the metal ion and a tail-mediated recognition of the middle/top area of the active site cavity. Compound 5e (R = 2-Cl) demonstrated relevant selectivity toward brain-expressed hCA VII. The best balancing in binding affinity and selectivity toward tumor-expressed hCA IX/hCA XII over ubiquitous hCA I/hCA II was found for inhibitor 5o (R = 3-NO(2)). Notably 5b (R = 2-F) proved to be the most efficacious inhibitor of hCA XII for which computational studies elucidated the CA recognition process. Looking toward the Rim of the Active Site Cavity of Druggable Human Carbonic Anhydrase Isoforms.,Mancuso F, Di Fiore A, De Luca L, Angeli A, Monti SM, De Simone G, Supuran CT, Gitto R ACS Med Chem Lett. 2020 Mar 4;11(5):1000-1005. doi: , 10.1021/acsmedchemlett.0c00062. eCollection 2020 May 14. PMID:32435417[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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