Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX(653 views) Alterio V, Hilvo M, Di Fiore A, Supuran CT, Pan P, Parkkila S, Scaloni A, Pastorek J, Pastorekova S, Pedone C, Scozzafava A, Monti SM, De Simone G
P Natl Acad Sci Usa (ISSN: 0027-8424, 1091-6490, 0027-8424print), 2009 Sep 22; 106(38): 16233-16238.
Istituto di Biostrutture e Bioimmagini-CNR, via Mezzocannone 16, 80134 Naples, Italy
Institute of Medical Technology, University of Tampere, Tampere University Hospital, FI-33014 Tampere, Finland
VTT Technical Research Centre of Finland, Tietotie 2, P.O. Box 1000, FI-02044 VTT, Espoo, Finland
Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Polo Scientifico, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy
Proteomics and Mass Spectrometry Laboratory, ISPAAM-CNR, via Argine 1085, 80147 Naples, Italy
Institute of Virology, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia
References: Not available.
Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX
Carbonic anhydrase (CA) IX is a plasma membrane-associated member of the α-CA enzyme family, which is involved in solid tumor acidification. It is a marker of tumor hypoxia and a prognostic factor in several human cancers. An aberrant increase in CA IX expression in chronic hypoxia and during development of various carcinomas contributes to tumorigenesis through at least two mechanisms: pH regulation and cell adhesion control. Here we report the X-ray structure of the catalytic domain of CA IX in complex with a classical, clinically used sulfonamide inhibitor, acetazolamide. The structure reveals a typical α-CA fold, which significantly differs from the other CA isozymes when the protein quaternary structure is considered. Thus, two catalytic domains of CA IX associate to form a dimer, which is stabilized by the formation of an intermolecular disulfide bond. The active site clefts and the PG domains are located on one face of the dimer, while the C-termini are located on the opposite face to facilitate protein anchoring to the cell membrane. A correlation between the three-dimensional structure and the physiological role of the enzyme is here suggested, based on the measurement of the pH profile of the catalytic activity for the physiological reaction, CO2 hydration to bicarbonate and protons. On the basis of the structural differences observed between CA IX and the other membrane-associated α-CAs, further prospects for the rational drug design of isozyme-specific CA inhibitors are proposed, given that inhibition of this enzyme shows antitumor activity both in vitro and in vivo.
Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX
Vitiello M, Finamore E, Falanga A, Raieta K, Cantisani M, Galdiero F, Pedone C, Galdiero M, Galdiero S * Fusion in Coq(562 views) Lecture Notes In Computer Science (ISSN: 0302-9743, 0302-974335404636319783540463634, 0302-974335402975459783540297543), 2001; 2178LNCS: 583-596. Impact Factor:0.415 ViewExport to BibTeXExport to EndNote