4IWZ: Structure of Hcaii in Complex With an Acetazolamide Derivative

Citation:
Abstract
The high resolution crystal structure of 5-(2-thienylacetamido)-1,3,4-thiadiazole-2-sulfonamide complexed to human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoform hCA II is reported. The compound binds in a similar manner with acetazolamide when the sulfamoyl-thiadiazolyl-acetamido fragment of the two compounds is considered, but the thienyl tail was positioned in the subpocket 2, rarely observed by other investigated CA inhibitors. This positioning allows interaction with amino acid residues (such as Asn67, Ile91, Gln92 and Val121 which are variable in other isoforms of medicinal chemistry interest, such as hCA I, IX and XII. Indeed, the investigated sulfonamide was a medium potency hCA I and II inhibitor but was highly effective as a hCA IX and XII inhibitor. This different behavior with respect to acetazolamide (a promiscuous inhibitor of all these isoforms) has been explained by resolving the crystal structure, and may be used to design more isoform-selective compounds.
PDB ID: 4IWZDownload
MMDB ID: 115841
PDB Deposition Date: 2013/1/24
Updated in MMDB: 2013/12
Experimental Method:
x-ray diffraction
Resolution: 1.6  Å
Source Organism:
Similar Structures:
Biological Unit for 4IWZ: monomeric; determined by author and by software (PISA)
Molecular Components in 4IWZ
Label Count Molecule
Protein (1 molecule)
1
Carbonic Anhydrase 2
Molecule annotation
Chemicals (6 molecules)
1
1
2
1
3
3
4
1
* Click molecule labels to explore molecular sequence information.

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