4R5B

Human Carbonic Anhydrase II in Complex with a Carbohydrate-Based Sulfamate

Summary for 4R5B

• Entry DOI: 10.2210/pdb4r5b/pdb
• Related: 4R59 4R5A
• Descriptor: Carbonic anhydrase 2, ZINC ION, GLYCEROL, ... (5 entities in total)
• Functional Keywords: cytosol, lyase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 29838.97

Authors

Mahon, B.P.,McKenna, R. (deposition date: 2014-08-20, release date: 2014-10-15, Last modification date: 2023-09-20)

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

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: 25254302
DOI: 10.1021/jm5012935

Experimental method

X-RAY DIFFRACTION (1.5 Å)