4KV0

Crystal structure of human carbonic anhydrase II in complex with the 5-(3-tosylureido)pyridine-2-sulfonamide inhibitor

Summary for 4KV0

• Entry DOI: 10.2210/pdb4kv0/pdb
• Related: 4KUV 4KUW 4KUY
• Descriptor: Carbonic anhydrase 2, ZINC ION, GLYCEROL, ... (6 entities in total)
• Functional Keywords: lyase, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : P00918
• Total number of polymer chains: 1
• Total formula weight: 29538.68

Authors

Ferraroni, M. (deposition date: 2013-05-22, release date: 2014-06-25, Last modification date: 2023-09-20)

Primary citation

Bozdag, M.,Ferraroni, M.,Nuti, E.,Vullo, D.,Rossello, A.,Carta, F.,Scozzafava, A.,Supuran, C.T.
Combining the tail and the ring approaches for obtaining potent and isoform-selective carbonic anhydrase inhibitors: solution and X-ray crystallographic studies.
Bioorg.Med.Chem., 22:334-340, 2014

PubMed Abstract: 5-(3-Tosylureido)pyridine-2-sulfonamide and 4-tosylureido-benzenesulfonamide (ts-SA) only differ by the substitution of a CH by a nitrogen atom, but they have very different inhibitory properties against the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). By means of X-ray crystallography on the human CA II adducts of the two compounds these differences have been rationalized. As all sulfonamides, the two compounds bind in deprotonated form to the Zn(II) ion from the enzyme active site and their organic scaffolds extend throughout the cavity, participating in many interactions with amino acid residues and water molecules. However the pyridine derivative undergoes a tilt of the heterocyclic ring compared to the benzene analog, which leads to a very different orientation of the two scaffolds when bound to the enzyme. This tilt also leads to a clash between a carbon atom from the pyridine ring of the first inhibitor and the OH moiety of Thr200, leading to less effective inhibitory properties of the pyridine versus the benzene sulfonamide derivative. Indeed, ts-SA is a promiscuous, low nanomolar inhibitor of 7 out of 10 human (h) CA isoforms, whereas the pyridine sulfonamide is a low nanomolar inhibitor only of the tumor-associated hCA IX and XII, being less effective against other 9 isoforms. Thus, a difference of one atom (N vs CH) in two isostructural sulfonamides leads to drastic differences of activity, phenomenon understood at the atomic level through the high resolution crystallographic structure and kinetic measurements reported in the paper. Combining the tail and the ring approaches in the same chemotype leads to isoform-selective, highly effective sulfonamide CA inhibitors.

PubMed: 24300919
DOI: 10.1016/j.bmc.2013.11.016

Experimental method

X-RAY DIFFRACTION (1.55 Å)