3KWA

Polyamines inhibit carbonic anhydrases

Summary for 3KWA

• Entry DOI: 10.2210/pdb3kwa/pdb
• Descriptor: Carbonic anhydrase 2, ZINC ION, MERCURY (II) ION, ... (5 entities in total)
• Functional Keywords: polyamines, carbonic anhydrase ii, inhibition, lyase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : P00918
• Total number of polymer chains: 1
• Total formula weight: 29757.40

Authors

Temperini, C. (deposition date: 2009-12-01, release date: 2010-07-14, Last modification date: 2023-11-01)

Primary citation

Carta, F.,Temperini, C.,Innocenti, A.,Scozzafava, A.,Kaila, K.,Supuran, C.T.
Polyamines inhibit carbonic anhydrases by anchoring to the zinc-coordinated water molecule
J.Med.Chem., 53:5511-5522, 2010

PubMed Abstract: Carbonic anhydrases (CAs, EC 4.2.1.1) are inhibited by sulfonamides, phenols, and coumarins. Polyamines such as spermine, spermidine, and many synthetic congeners are described to constitute a novel class of CA inhibitors (CAIs), interacting with the different CA isozymes with efficiency from the low nanomolar to millimolar range. The main structure-activity relationship for these CAIs have been delineated: the length of the molecule, number of amine moieties, and their functionalization are the main parameters controlling activity. The X-ray crystal structure of the CA II-spermine adduct allowed understanding of the inhibition mechanism. Spermine anchors to the nonprotein zinc ligand through a network of hydrogen bonds. Its distal amine moiety makes hydrogen bonds with residues Thr200 and Pro201, which further stabilize the adduct. Spermine binds differently compared to sulfonamides, phenols, or coumarins, rendering possible to develop CAIs with a diverse inhibition mechanism, profile, and selectivity for various isoforms.

PubMed: 20590092
DOI: 10.1021/jm1003667

Experimental method

X-RAY DIFFRACTION (2 Å)