2NNO

Structure of inhibitor binding to Carbonic Anhydrase II

2NNO の概要

• エントリーDOI: 10.2210/pdb2nno/pdb
• 関連するPDBエントリー: 2NMX 2NN1 2NN7 2NNG 2NNS 2NNV
• 分子名称: Carbonic anhydrase 2, ZINC ION, 3-[4-(AMINOSULFONYL)PHENYL]PROPANOIC ACID, ... (5 entities in total)
• 機能のキーワード: zinc metalloenzyme, sulfonamide, lyase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 30119.69

構造登録者

Christianson, D.W.,Jude, K.M. (登録日: 2006-10-24, 公開日: 2007-05-08, 最終更新日: 2024-10-09)

主引用文献

Srivastava, D.K.,Jude, K.M.,Banerjee, A.L.,Haldar, M.,Manokaran, S.,Kooren, J.,Mallik, S.,Christianson, D.W.
Structural Analysis of Charge Discrimination in the Binding of Inhibitors to Human Carbonic Anhydrases I and II.
J.Am.Chem.Soc., 129:5528-5537, 2007

PubMed Abstract: 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.

PubMed: 17407288
DOI: 10.1021/ja068359w

実験手法

X-RAY DIFFRACTION (1.01 Å)