2hd6

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spinqualitylabelsall models PDB ID 2hd6 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image
, resolution 1.80Å
Ligands:	, , , and
Activity:	Carbonate dehydratase, with EC number 4.2.1.1
Coordinates:	save as pdb, mmCIF, xml

Crystal structure of the human carbonic anhydrase II in complex with a hypoxia-activatable sulfonamide.

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

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.

Disease

Known disease associated with this structure: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis OMIM:[611492]

About this Structure

2HD6 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Carbonic anhydrase inhibitors: Hypoxia-activatable sulfonamides incorporating disulfide bonds that target the tumor-associated isoform IX., De Simone G, Vitale RM, Di Fiore A, Pedone C, Scozzafava A, Montero JL, Winum JY, Supuran CT, J Med Chem. 2006 Sep 7;49(18):5544-51. PMID:16942027

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