1bv3

HUMAN CARBONIC ANHYDRASE II COMPLEXED WITH UREA

spinqualitylabelsall models 1bv3, resolution 1.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1bv3 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.85Å Ligands: HGB, URE, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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. 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. 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 PubMed The interaction of human carbonic anhydrase (hCA) isozymes I and II with cyanamide, a linear molecule isoelectronic with the main physiological substrate of the enzyme, CO(2), was investigated through spectroscopic, kinetic, and X-ray crystallographic studies. We show here that cyanamide is hydrated to urea in the presence of CAs, and that it also acts as a weak non-competitive inhibitor (K(I)=61+/-3 mM and 238+/-9 mM for hCA II and hCA I, respectively) towards the esterasic activity of these enzymes, as tested with 4-nitrophenyl acetate. Changes in the spectrum of the Co(II)-hCA II derivative observed in the presence of cyanamide suggest that it likely binds the metal ion within the CA active site, adding to the coordination sphere, not substituting the metal-bound solvent molecule. It thereafter undergoes a nucleophilic attack from the metal-bound hydroxide ion, forming urea which remains bound to the metal, as observed in the X-ray crystal structure of hCA II soaked in cyanamide solutions for several hours. The urea molecule is directly coordinated to the active site Zn(II) ion through a protonated nitrogen atom. Several hydrogen bonds involving active site residues Thr199 and Thr200 as well as three water molecules (Wat99, Wat122, and Wat123) further stabilize the urea-hCA II adduct. Kinetic studies in solution further proved that urea acts as a tight binding inhibitor of the two isozymes hCA I and hCA II, with very slow binding kinetics (k(on) = 2.5 x 10(-5)s(-1)M(-1)). A mechanism to explain the hydration process of cyanamide by CAs, as well as the tight binding of urea in the active site, is also proposed based on the hypothesis that urea is deprotonated when bound to the enzyme. Cyanamide is thus the first true suicide substrate of this enzyme for which binding has been documented by means of X-ray crystallographic and spectroscopic studies. Carbonic anhydrase catalyzes cyanamide hydration to urea: is it mimicking the physiological reaction?,Briganti F, Mangani S, Scozzafava A, Vernaglione G, Supuran CT J Biol Inorg Chem. 1999 Oct;4(5):528-36. PMID:10550681 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Carbonic anhydrase 3D structures

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