3DCS

Use of Carbonic Anhydrase II, IX Active-Site Mimic, for the Purpose of Screening Inhibitors for Possible Anti-Cancer Properties

Summary for 3DCS

• Entry DOI: 10.2210/pdb3dcs/pdb
• Related: 3D8W 3DAZ 3DBU 3DC3 3DC9 3DCC 3DCW 3DD0
• Descriptor: Carbonic anhydrase 2, ZINC ION, N-(3-methyl-5-sulfamoyl-1,3,4-thiadiazol-2(3H)-ylidene)acetamide, ... (4 entities in total)
• Functional Keywords: carbonic anhydrase ii complex, caix mimic inhibitors, disease mutation, lyase, metal-binding
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : P00918
• Total number of polymer chains: 1
• Total formula weight: 29620.77

Authors

Genis, C.,Sippel, K.H.,Case, N.,Govindasamy, L.,Agbandje-Mckenna, M.,Mckenna, R. (deposition date: 2008-06-04, release date: 2009-03-03, Last modification date: 2023-08-30)

Primary citation

Genis, C.,Sippel, K.H.,Case, N.,Cao, W.,Avvaru, B.S.,Tartaglia, L.J.,Govindasamy, L.,Tu, C.,Agbandje-McKenna, M.,Silverman, D.N.,Rosser, C.J.,McKenna, R.
Design of a carbonic anhydrase IX active-site mimic to screen inhibitors for possible anticancer properties
Biochemistry, 48:1322-1331, 2009

PubMed Abstract: Recently, a convincing body of evidence has accumulated suggesting that the overexpression of carbonic anhydrase isozyme IX (CA IX) in some cancers contributes to the acidification of the extracellular matrix, which in turn promotes the growth and metastasis of the tumor. These observations have made CA IX an attractive drug target for the selective treatment of certain cancers. Currently, there is no available X-ray crystal structure of CA IX, and this lack of availability has hampered the rational design of selective CA IX inhibitors. In light of these observations and on the basis of structural alignment homology, using the crystal structure of carbonic anhydrase II (CA II) and the sequence of CA IX, a double mutant of CA II with Ala65 replaced by Ser and Asn67 replaced by Gln has been constructed to resemble the active site of CA IX. This CA IX mimic has been characterized kinetically using (18)O-exchange and structurally using X-ray crystallography, alone and in complex with five CA sulfonamide-based inhibitors (acetazolamide, benzolamide, chlorzolamide, ethoxzolamide, and methazolamide), and compared to CA II. This structural information has been evaluated by both inhibition studies and in vitro cytotoxicity assays and shows a correlated structure-activity relationship. Kinetic and structural studies of CA II and CA IX mimic reveal chlorzolamide to be a more potent inhibitor of CA IX, inducing an active-site conformational change upon binding. Additionally, chlorzolamide appears to be cytotoxic to prostate cancer cells. This preliminary study demonstrates that the CA IX mimic may provide a useful model to design more isozyme-specific CA IX inhibitors, which may lead to development of new therapeutic treatments of some cancers.

PubMed: 19170619
DOI: 10.1021/bi802035f

Experimental method

X-RAY DIFFRACTION (1.8 Å)