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Publikācija: Efficient Expression and Crystallization System of Cancer-Associated Carbonic Anhydrase Isoform IX

Publication Type Scientific article indexed in SCOPUS or WOS database
Funding for basic activity Unknown
Defending: ,
Publication language English (en)
Title in original language Efficient Expression and Crystallization System of Cancer-Associated Carbonic Anhydrase Isoform IX
Field of research 1. Natural sciences
Sub-field of research 1.4 Chemical sciences
Authors Jekaterīna Ivanova
Agnese Balode
Raivis Žalubovskis
Kaspars Tārs
Andris Kazaks
Janis Leitans
Claudiu T. Supuran
Keywords
Abstract Human carbonic anhydrase IX (CA IX) is overexpressed in a number of solid tumors and is considered to be a marker for cellular hypoxia that it is not produced in most normal tissues. CA IX contributes to the acidification of the extracellular matrix, which, in turn, favors tumor growth and metastasis. Therefore, CA IX is considered to be a promising anti-cancer drug target. However, the ability to specifically target CA IX is challenging due to the fact that the human genome encodes 15 different carbonic anhydrase isoforms that have a high degree of homology. Furthermore, structure-based drug design of CA IX inhibitors so far has been largely unsuccessful due to technical difficulties regarding the expression and crystallization of the enzyme. Currently, only one baculovirus-produced CA IX structure in complex with a nonspecific CA inhibitor, acetazolamide, is available in Protein Data Bank. We have developed an efficient system for the production of the catalytic domain of CA IX in methylotrophic yeast Pichia pastoris. The produced protein can be easily crystallized in the presence of inhibitors, as we have demonstrated for several 2-thiophene-sulfonamide compounds. We have also observed significant differences in the binding mode of chemically identical compounds to CA IX and CA II, which can be further exploited in the design of CA IX-specific inhibitors.
DOI: 10.1021/acs.jmedchem.5b01343
Hyperlink: http://pubs.acs.org/doi/10.1021/acs.jmedchem.5b01343 
Reference Ivanova, J., Balode, A., Žalubovskis, R., Tārs, K., Kazaks, A., Leitans, J., Supuran, C. Efficient Expression and Crystallization System of Cancer-Associated Carbonic Anhydrase Isoform IX. Journal of Medicinal Chemistry, 2015, Vol.58, No.22, pp.9004-9009. ISSN 0022-2623. Available from: doi:10.1021/acs.jmedchem.5b01343
Additional information Citation count:
ID 24040