2nnv
Structure of inhibitor binding to Carbonic Anhydrase II
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OverviewOverview
Despite the similarity in the active site pockets of carbonic anhydrase, (CA) isozymes I and II, the binding affinities of benzenesulfonamide, inhibitors are invariably higher with CA II as compared to CA I. To, explore the structural basis of this molecular recognition phenomenon, we, have designed and synthesized simple benzenesulfonamide inhibitors, substituted at the para position with positively charged, negatively, charged, and neutral functional groups, and we have determined the, affinities and X-ray crystal structures of their enzyme complexes. The, para-substituents are designed to bind in the midsection of the 15 A deep, active site cleft, where interactions with enzyme residues and solvent, molecules are possible. We find that a para-substituted positively charged, amino group is more poorly tolerated in the active site of CA I compared, with CA II. In contrast, a para-substituted negatively charged carboxylate, substituent is tolerated equally well in the active sites of both CA, isozymes. Notably, enzyme-inhibitor affinity increases upon neutralization, of inhibitor charged groups by amidation or esterification. These results, inform the design of short molecular linkers connecting the, benzenesulfonamide group and a para-substituted tail group in "two-prong", CA inhibitors: an optimal linker segment will be electronically neutral, yet capable of engaging in at least some hydrogen bond interactions with, protein residues and/or solvent. Microcalorimetric data reveal that, inhibitor binding to CA I is enthalpically less favorable and entropically, more favorable than inhibitor binding to CA II. This contrasting behavior, may arise in part from differences in active site desolvation and the, conformational entropy of inhibitor binding to each isozyme active site.
DiseaseDisease
Known disease associated with this structure: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis OMIM:[611492]
About this StructureAbout this Structure
2NNV is a Single protein structure of sequence from Homo sapiens with ZN, M29 and GOL as ligands. Active as Carbonate dehydratase, with EC number 4.2.1.1 Full crystallographic information is available from OCA.
ReferenceReference
Structural Analysis of Charge Discrimination in the Binding of Inhibitors to Human Carbonic Anhydrases I and II., Srivastava DK, Jude KM, Banerjee AL, Haldar M, Manokaran S, Kooren J, Mallik S, Christianson DW, J Am Chem Soc. 2007 Apr 4;. PMID:17407288
Page seeded by OCA on Mon Nov 12 23:00:19 2007