4R5A
A Carbonic Anhydrase IX Mimic in Complex with a Carbohydrate-Based Sulfamate
Summary for 4R5A
| Entry DOI | 10.2210/pdb4r5a/pdb |
| Related | 4R59 4R5B |
| Descriptor | Carbonic anhydrase 2, ZINC ION, GLYCEROL, ... (5 entities in total) |
| Functional Keywords | carbonic anhydrase ix mimic, lyase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 29791.82 |
| Authors | Mahon, B.P.,McKenna, R. (deposition date: 2014-08-20, release date: 2014-10-15, Last modification date: 2024-10-09) |
| Primary citation | Moeker, J.,Mahon, B.P.,Bornaghi, L.F.,Vullo, D.,Supuran, C.T.,McKenna, R.,Poulsen, S.A. Structural Insights into Carbonic Anhydrase IX Isoform Specificity of Carbohydrate-Based Sulfamates. J.Med.Chem., 57:8635-8645, 2014 Cited by PubMed Abstract: Carbonic anhydrase IX (CA IX) is an extracellular transmembrane homodimeric zinc metalloenzyme that has been validated as a prognostic marker and therapeutic target for several types of aggressive cancers. CA IX shares a close homology with other CA isoforms, making the design of CA IX isoform selective inhibitors challenging. In this paper, we describe the development of a new class of CA IX inhibitors that comprise a sulfamate as the zinc binding group, a variable linker, and a carbohydrate "tail" moiety. Seven compounds inhibited CA IX with low nM Ki values of 1-2 nM and also exhibited permeability profiles to preferentially target the binding of extracellular CA IX over cytosolic CAs. The crystal structures of two of these compounds in complex with a CA IX-mimic (a variant of CA II, with active site residues that mimic CA IX) and one compound in complex with CA II have been determined to 1.7 Å resolution or better and demonstrate a selective mechanism of binding between the hydrophilic and hydrophobic pockets of CA IX versus CA II. These compounds present promising candidates for anti-CA IX drugs and the treatment for several aggressive cancer types. PubMed: 25254302DOI: 10.1021/jm5012935 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.64 Å) |
Structure validation
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