4QJM

Crystal structure of human carbonic anhydrase isozyme II with inhibitor

Summary for 4QJM

• Entry DOI: 10.2210/pdb4qjm/pdb
• Related: 4QIY 4QIZ 4QJ0 4QJO 4QJP 4QJW 4QJX 4QTL
• Descriptor: Carbonic anhydrase 2, ZINC ION, 3-(benzylamino)-2,5,6-trifluoro-4-[(2-phenylethyl)sulfonyl]benzenesulfonamide, ... (7 entities in total)
• Functional Keywords: drug design, carbonic anhydrase, benzenesulfonamide, metal-binding, 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: 30275.53

Authors

Smirnov, A.,Manakova, E.,Grazulis, S. (deposition date: 2014-06-04, release date: 2015-04-15, Last modification date: 2023-11-08)

Primary citation

Dudutiene, V.,Zubriene, A.,Smirnov, A.,Timm, D.D.,Smirnoviene, J.,Kazokaite, J.,Michailoviene, V.,Zaksauskas, A.,Manakova, E.,Grazulis, S.,Matulis, D.
Functionalization of Fluorinated Benzenesulfonamides and Their Inhibitory Properties toward Carbonic Anhydrases
Chemmedchem, 10:662-687, 2015

PubMed Abstract: Substituted tri- and tetrafluorobenzenesulfonamides were designed, synthesized, and evaluated as high-affinity and isoform-selective carbonic anhydrase (CA) inhibitors. Their binding affinities for recombinant human CA I, II, VA, VI, VII, XII, and XIII catalytic domains were determined by fluorescent thermal shift assay, isothermal titration calorimetry, and a stopped-flow CO2 hydration assay. Variation of the substituents at the 2-, 3-, and 4-positions yielded compounds with a broad range of binding affinities and isoform selectivities. Several 2,4-substituted-3,5,6-trifluorobenzenesulfonamides were effective CA XIII inhibitors with high selectivity over off-target CA I and CA II. 3,4-Disubstituted-2,5,6-trifluorobenzenesulfonamides bound CAs with higher affinity than 2,4-disubstituted-3,5,6-trifluorobenzenesulfonamides. Many such fluorinated benzenesulfonamides were found to be nanomolar inhibitors of CA II, CA VII, tumor-associated CA IX and CA XII, and CA XIII. X-ray crystal structures of inhibitors bound in the active sites of several CA isoforms provide structure-activity relationship information for inhibitor binding affinities and selectivity.

PubMed: 25758852
DOI: 10.1002/cmdc.201402490

Experimental method

X-RAY DIFFRACTION (1.75 Å)