4IWZ

structure of hCAII in complex with an acetazolamide derivative

Summary for 4IWZ

• Entry DOI: 10.2210/pdb4iwz/pdb
• Descriptor: Carbonic anhydrase 2, N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)-2-(thiophen-2-yl)acetamide, ZINC ION, ... (6 entities in total)
• Functional Keywords: alpha beta fold, reversible hydration of carbon di oxide to bicarbonate and proton, 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: 29656.83

Authors

Biswas, S.,McKenna, R. (deposition date: 2013-01-24, release date: 2013-12-11, Last modification date: 2024-02-28)

Primary citation

Biswas, S.,McKenna, R.,Supuran, C.T.
Effect of incorporating a thiophene tail in the scaffold of acetazolamide on the inhibition of human carbonic anhydrase isoforms I, II, IX and XII.
Bioorg.Med.Chem.Lett., 23:5646-5649, 2013

PubMed 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.

PubMed: 23993330
DOI: 10.1016/j.bmcl.2013.08.019

Experimental method

X-RAY DIFFRACTION (1.598 Å)