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3mnj

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3mnj, resolution 1.75Å ()
Ligands: ,
Gene: CA2 (Homo sapiens)
Activity: Carbonate dehydratase, with EC number 4.2.1.1
Related: 3mnh, 3mni, 3mnk


Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

Human Carbonic Anhydrase II Mutant K170E

Publication Abstract from PubMed

The catalysis of CO(2) hydration by human carbonic anhydrase II (HCA II) is limited in maximal velocity by proton transfer from a zinc-bound water molecule to the proton shuttle His64. This proton transfer occurs along a hydrogen-bonded water network, leading to the proton shuttle residue His64, which in turn transfers the proton to bulk solvent. The side chain of His64 occupies two conformations in wild-type HCA II, pointing inward toward the zinc or outward toward bulk solvent. Previously, several studies have examined the roles of residues of the active site cavity that interact with the solvent-mediated hydrogen-bonded network between His64 and the zinc-bound water. Here these studies are extended to examine the effects on proton transfer by mutation at Lys170 (to Ala, Asp, Glu, and His), a residue located near the side chain of His64 but over 15 A away from the active site zinc. In all four variants, His64 is observed in the inward conformation associated with a decrease in the pK(a) of His64 by as much as 1.0 unit and an increase in the rate constant for proton transfer to as much as 4 mus(-1), approximately 5-fold larger than wild-type HCA II. The results show a significant extension of the effective active site of HCA II from the zinc-bound water at the base of the conical cavity in the enzyme to Lys170 near the rim of the cavity. These data emphasize that the active site of HCA II is extended to include residues that, at first glance, appear to be too far from the zinc to exert any catalytic effects.

Structural and Kinetic Study of the Extended Active Site for Proton Transfer in Human Carbonic Anhydrase II., Domsic JF, Williams W, Fisher SZ, Tu C, Agbandje-McKenna M, Silverman DN, McKenna R, Biochemistry. 2010 Jul 9. PMID:20578724

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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]

About this Structure

3mnj is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

See Also

Reference

  • Domsic JF, Williams W, Fisher SZ, Tu C, Agbandje-McKenna M, Silverman DN, McKenna R. Structural and Kinetic Study of the Extended Active Site for Proton Transfer in Human Carbonic Anhydrase II. Biochemistry. 2010 Jul 9. PMID:20578724 doi:10.1021/bi1007645
  1. 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
  2. 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
  3. 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
  4. 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
  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
  6. 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
  7. 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

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