6hqx

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Human Carbonic Anhydrase II in complex with 4-EthylbenzenesulfonamideHuman Carbonic Anhydrase II in complex with 4-Ethylbenzenesulfonamide

Structural highlights

6hqx 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 1.097Å
Ligands:, , , ,
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.[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]

Publication Abstract from PubMed

Thermodynamics and kinetics of protein-ligand binding are both important aspects for the design of novel drug molecules. Presently, thermodynamic data are collected with isothermal titration calorimetry, while kinetic data are mostly derived from surface plasmon resonance. The new method of kinITC provides both thermodynamic and kinetic data from calorimetric titration measurements. The present study demonstrates the convenient collection of calorimetric data suitable for both thermodynamic and kinetic analysis for two series of congeneric ligands of human carbonic anhydrase II and correlates these findings with structural data obtained by macromolecular crystallography to shed light on the importance of shape complementarity for thermodynamics and kinetics governing a protein-ligand binding event. The study shows how minute chemical alterations change preferred ligand conformation and can be used to manipulate thermodynamic and kinetic signatures of binding. They give rise to the observation that analogous n-alkyl and n-alkyloxy derivatives of identical chain length swap their binding kinetic properties at unchanged binding affinity.

Conformational Changes in Alkyl Chains Determine the Thermodynamic and Kinetic Binding Profiles of Carbonic Anhydrase Inhibitors.,Glockner S, Ngo K, Sager CP, Hufner-Wulsdorf T, Heine A, Klebe G ACS Chem Biol. 2020 Mar 20;15(3):675-685. doi: 10.1021/acschembio.9b00895. Epub, 2020 Feb 19. PMID:32027480[8]

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

See Also

References

  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
  8. ↑ Glockner S, Ngo K, Sager CP, Hufner-Wulsdorf T, Heine A, Klebe G. Conformational Changes in Alkyl Chains Determine the Thermodynamic and Kinetic Binding Profiles of Carbonic Anhydrase Inhibitors. ACS Chem Biol. 2020 Mar 20;15(3):675-685. doi: 10.1021/acschembio.9b00895. Epub, 2020 Feb 19. PMID:32027480 doi:http://dx.doi.org/10.1021/acschembio.9b00895

6hqx, resolution 1.10Å

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