2HD6: Crystal Structure of the Human Carbonic Anhydrase II in Complex With a Hypoxia-activatable Sulfonamide

Citation:
Abstract
An approach for designing bioreductive, hypoxia-activatable carbonic anhydrase (CA, EC 4.2.1.1) inhibitors targeting the tumor-associated isoforms is reported. Sulfonamides incorporating 3,3'-dithiodipropionamide/2,2'-dithiodibenzamido moieties were prepared and reduced enzymatically/chemically in conditions present in hypoxic tumors, leading to thiols. The X-ray crystal structure of the most promising compound, 4-(2-mercaptophenylcarboxamido)benzenesulfonamide, which as disulfide showed a K(I) against hCA IX of 653 nM (in reduced form of 9.1 nM), in adduct with hCA II showed the inhibitor making favorable interactions with Gln92, Val121, Phe131, Leu198, Thr199, Thr200, Pro201, and Pro202, whereas the sulfamoyl moiety was coordinated to the Zn2+ ion. The same interactions were preserved in the adduct with hCA IX, but in addition, a hydrogen bond between the SH moiety of the inhibitor and the amide nitrogen of Gln67 was evidenced, which may explain the almost 2 times more effective inhibition of the tumor-associated isozyme over the cytosolic isoform.
PDB ID: 2HD6Download
MMDB ID: 41623
PDB Deposition Date: 2006/6/20
Updated in MMDB: 2011/10 
Experimental Method:
x-ray diffraction
Resolution: 1.8  Å
Source Organism:
Similar Structures:
Biological Unit for 2HD6: monomeric; determined by author
Molecular Components in 2HD6
Label Count Molecule
Protein (1 molecule)
1
Carbonic Anhydrase 2
Molecule annotation
Chemicals (5 molecules)
1
1
2
1
3
1
4
1
5
1
* Click molecule labels to explore molecular sequence information.

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