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|1cny, resolution 2.30Å ()|
SECONDARY INTERACTIONS SIGNIFICANTLY REMOVED FROM THE SULFONAMIDE BINDING POCKET OF CARBONIC ANHYDRASE II INFLUENCE BINDING CONSTANTS
A series of competitive inhibitors of carbonic anhydrase II (CAII; EC 126.96.36.199) that consists of oligo(ethylene glycol) units attached to p-benzenesulfonamides with pendant amino acids, H2NSO2C6H4CONHCH2CH2OCH2CH2OCH2CH2NHCOCHRNH3+, have been synthesized and examined using competitive fluorescence assays. Three of the strongest inhibitors, designated EG3NH3+, EG3GlyNH3+, and EG3PheNH3+, have been studied by X-ray crystallographic methods at limiting resolutions of 1.9, 2.0, and 2.3 A, respectively. The sulfonamide-zinc binding modes and the association of the ethylene glycol linkers to the hydrophobic patch of the active site are similar in all three inhibitors. Differences in the values of Kd are therefore not due to differences in zinc coordination or to differences in the modes of enzyme-glycol association but instead appear to arise from interaction of the pendant amino acids with the surface of the protein. These pendant groups are, however, not sufficiently ordered to be visible in electron density maps. Thus, structural variations of inhibitors at locations distant from the primary binding (i.e., the sulfonamide group) site affect the overall binding affinities of inhibitors (e.g., Kd (EG3PheNH3+) = 14 nM as compared with Kd (EG3GluNH3+) = 100 nM).
Secondary interactions significantly removed from the sulfonamide binding pocket of carbonic anhydrase II influence inhibitor binding constants., Boriack PA, Christianson DW, Kingery-Wood J, Whitesides GM, J Med Chem. 1995 Jun 23;38(13):2286-91. PMID:7608893
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[CAH2_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.
[CAH2_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.
About this Structure
- Boriack PA, Christianson DW, Kingery-Wood J, Whitesides GM. Secondary interactions significantly removed from the sulfonamide binding pocket of carbonic anhydrase II influence inhibitor binding constants. J Med Chem. 1995 Jun 23;38(13):2286-91. PMID:7608893
- ↑ Venta PJ, Welty RJ, Johnson TM, Sly WS, Tashian RE. Carbonic anhydrase II deficiency syndrome in a Belgian family is caused by a point mutation at an invariant histidine residue (107 His----Tyr): complete structure of the normal human CA II gene. Am J Hum Genet. 1991 Nov;49(5):1082-90. PMID:1928091
- ↑ Roth DE, Venta PJ, Tashian RE, Sly WS. Molecular basis of human carbonic anhydrase II deficiency. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1804-8. PMID:1542674
- ↑ Soda H, Yukizane S, Yoshida I, Koga Y, Aramaki S, Kato H. A point mutation in exon 3 (His 107-->Tyr) in two unrelated Japanese patients with carbonic anhydrase II deficiency with central nervous system involvement. Hum Genet. 1996 Apr;97(4):435-7. PMID:8834238
- ↑ Hu PY, Lim EJ, Ciccolella J, Strisciuglio P, Sly WS. Seven novel mutations in carbonic anhydrase II deficiency syndrome identified by SSCP and direct sequencing analysis. Hum Mutat. 1997;9(5):383-7. PMID:9143915 doi:<383::AID-HUMU1>3.0.CO;2-5 10.1002/(SICI)1098-1004(1997)9:5<383::AID-HUMU1>3.0.CO;2-5
- ↑ Shah GN, Bonapace G, Hu PY, Strisciuglio P, Sly WS. Carbonic anhydrase II deficiency syndrome (osteopetrosis with renal tubular acidosis and brain calcification): novel mutations in CA2 identified by direct sequencing expand the opportunity for genotype-phenotype correlation. Hum Mutat. 2004 Sep;24(3):272. PMID:15300855 doi:10.1002/humu.9266
- ↑ Briganti F, Mangani S, Scozzafava A, Vernaglione G, Supuran CT. Carbonic anhydrase catalyzes cyanamide hydration to urea: is it mimicking the physiological reaction? J Biol Inorg Chem. 1999 Oct;4(5):528-36. PMID:10550681
- ↑ Kim CY, Whittington DA, Chang JS, Liao J, May JA, Christianson DW. Structural aspects of isozyme selectivity in the binding of inhibitors to carbonic anhydrases II and IV. J Med Chem. 2002 Feb 14;45(4):888-93. PMID:11831900