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STRUCTURAL BASIS OF INHIBITOR AFFINITY TO VARIANTS OF HUMAN CARBONIC ANHYDRASE IISTRUCTURAL BASIS OF INHIBITOR AFFINITY TO VARIANTS OF HUMAN CARBONIC ANHYDRASE II
Structural highlights
Disease[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.[1] [2] [3] [4] [5] Function[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.[6] [7] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe activities and structures of certain L198 variants of human carbonic anhydrase II (CAII) have been reported recently [Krebs, J. F., Rana, F., Dluhy, R. A., & Fierke, C. A. (1993) Biochemistry 32, 4496-4505; Nair, S. K., & Christianson, D. W. (1993) Biochemistry 32, 4506-4514]. In order to understand the structural basis of enzyme-inhibitor affinity, we now report the dissociation rate and equilibrium constants for acetazolamide and dansylamide binding to 13 variants of CAII containing substituted amino acids at position 198. These data indicate that inhibitor affinity is modulated by the hydrophobicity and charge of the 198 side chain. Furthermore, we have determined crystal structures of L198R, L198E, and L198F CAIIs complexed with the transition state analog acetazolamide. The substituted benzyl side chain of L198F CAII does not occlude the substrate association pocket, and it is therefore not surprising that this substitution has minimal effects on catalytic properties and inhibitor binding. Nevertheless, the F198 side chain undergoes a significant conformation change in order to accommodate the binding of acetazolamide; the same behavior is observed for the engineered side chain of L198R CAII. In contrast, the engineered side chain of L198E CAII does not alter its conformation upon inhibitor binding. We conclude that the mobility and hydrophobicity or residue 198 side chains affect enzyme-inhibitor (and enzyme-substrate) affinity, and these structure-function relationships are important for understanding the behavior of carbonic anhydrase isozyme III, which bears a wild-type F198 side chain.(ABSTRACT TRUNCATED AT 250 WORDS) Structural basis of inhibitor affinity to variants of human carbonic anhydrase II.,Nair SK, Krebs JF, Christianson DW, Fierke CA Biochemistry. 1995 Mar 28;34(12):3981-9. PMID:7696263[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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